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  3. PubMed:19126755

PubMed: 19126755

Title
Mammalian nicotinic acetylcholine receptors: from structure to function.
Journal
Physiological reviews
Volume
89
Issue
None
Pages
73-120
Date
2009-01-01
Authors
Pereira EF | Alkondon M | Albuquerque EX | Rogers SW

Evidence 434d125975
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KYNA is formed enzymatically by the irreversible transamination of L-kynurenine, a major peripheral tryptophan metabolite with ready access to the brain. Immunohistochemical and lesion studies demonstrated that cerebral KYNA synthesis takes place almost exclusively in astrocytes (129, 187, 199).

a(CHEBI:"L-kynurenine") increases a(CHEBI:"kynurenic acid") View Subject | View Object

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Astrocytes
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Evidence 74caaaa29b
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A link between alpha4 nAChRs and Cox2 was suggested by the observation that interneurons in the hippocampus coexpress both proteins (165). A mechanistic connection was inferred when long-term treatment of aged animals with NS398 promoted retention of alpha4 nAChR expression in the brain, an effect that was antagonized by the coadministration of nicotine.

a(CHEBI:"NS-398") decreases p(HGNC:CHRNA4) View Subject | View Object

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a(CHEBI:nicotine) decreases act(a(CHEBI:"NS-398")) View Subject | View Object

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p(HGNC:CHRNA4) association p(HGNC:PTGS2) View Subject | View Object

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p(HGNC:PTGS2) association p(HGNC:CHRNA4) View Subject | View Object

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Evidence df63b40e95
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Other endogenous ligands that impact on the activity of nAChRs noncompetitively and voltage independently include the amyloid beta peptide 1-42 (Abeta1-42; Refs. 123, 376) and the canabinoid anandamide (356, 442).

a(CHEBI:"amyloid-beta polypeptide 42") association act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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a(CHEBI:anandamide) association act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) association a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) association a(CHEBI:anandamide) View Subject | View Object

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Evidence db1350f903
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It is noteworthy that the alpha7 nAChR activity increases intracellular accumulation of Abeta in neurons (336), and Abeta peptides, in addition to modulating nAChR activity, downregulate the expression of nAChRs (197).

a(CHEBI:"amyloid-beta polypeptide 42") regulates act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Neurons
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a(CHEBI:"amyloid-beta polypeptide 42") decreases r(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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Neurons
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act(p(HGNC:CHRNA7)) increases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

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Neurons
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Evidence 96c1da71cf
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The Abeta1-42 peptide is one of the breakdown products of the proteolytic cleavage of the amyloid precursor protein by beta- and gamma-secretases. In biopsy samples of human brain tissue obtained from AD patients and in ectopic systems overexpressing either alpha7 nAChRs or APP, Abeta1-42 coimmunoprecipitates with alpha7 nAChRs (490). The Abeta1-42 peptide also displaces binding of [3H]MLA from alpha7 nAChRs in cerebral cortical and hippocampal synaptosomes (490).

a(CHEBI:"amyloid-beta polypeptide 42") increases complex(a(CHEBI:"amyloid-beta polypeptide 42"), p(HGNC:CHRNA7)) View Subject | View Object

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Brain
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Alzheimer Disease
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a(CHEBI:"amyloid-beta polypeptide 42") decreases complex(a(MESH:methyllycaconitine), p(HGNC:CHRNA7)) View Subject | View Object

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Brain
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Alzheimer Disease
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p(HBP:"gamma-secretase") increases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

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p(HGNC:BACE1) increases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

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Evidence cf47b81135
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More functional studies reported that while at picomolar concentrations Abeta1-42 activates alpha7 nAChRs ectopically expressed in Xenopus oocytes (123, 126), at nanomolar concentrations it inhibits alpha7 nAChRs present in different preparations (278, 376). The alpha7 nAChR inhibition by Abeta1-42 is noncompetitive with respect to the agonist, is voltage independent, and is therefore likely to be mediated by the interaction of the peptide with a site different from that for ACh on the nAChRs.

a(CHEBI:"amyloid-beta polypeptide 42") decreases act(p(HGNC:CHRNA7)) View Subject | View Object

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Evidence a9f4211e4d
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Other studies have reported that alpha4beta2 nAChRs are more sensitive than alpha7 nAChRs to inhibition by nanomolar concentrations of Abeta1-42 (506).

a(CHEBI:"amyloid-beta polypeptide 42") decreases act(p(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

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Evidence 2f522538ff
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For example, during a low degree of activation of alpha7 and alpha3beta4 nAChRs, Ca2+ can enter the cells through nAChRs or NMDA receptors and favor activation (i.e., phosphorylation) of the transcription factor CREB, which in turn modifies gene expression (82).

a(CHEBI:"calcium(2+)", loc(GO:intracellular)) increases act(p(FPLX:CREB), ma(tscript)) View Subject | View Object

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act(p(HGNC:CHRNA7)) increases a(CHEBI:"calcium(2+)", loc(GO:intracellular)) View Subject | View Object

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act(p(HBP:"alpha-3 beta-4 nAChR")) increases a(CHEBI:"calcium(2+)", loc(GO:intracellular)) View Subject | View Object

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act(p(FPLX:CREB), ma(tscript)) regulates bp(GO:"gene expression") View Subject | View Object

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Evidence dad3a3787f
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There is evidence that anandamide is produced by postsynaptic neurons in response to elevated intracellular Ca2+ levels. For instance, concomitant activation of alpha7 nAChRs and NMDA receptors triggers the production of anandamine in postsynaptic neurons (448). Anandamine, then, functions as a retrograde messenger and regulates synaptic transmission by interacting with specific receptors in the presynaptic neurons/terminals (498).

a(CHEBI:"calcium(2+)", loc(GO:intracellular)) increases a(CHEBI:anandamide) View Subject | View Object

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Neurons
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a(CHEBI:anandamide) regulates bp(GO:"chemical synaptic transmission, postsynaptic") View Subject | View Object

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Neurons
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act(p(HGNC:CHRNA7)) increases a(CHEBI:anandamide) View Subject | View Object

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Neurons
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act(p(HGNCGENEFAMILY:"Glutamate ionotropic receptor NMDA type subunits")) increases a(CHEBI:anandamide) View Subject | View Object

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Neurons
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Evidence 06a01d77b0
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It was then recognized that Ca2+ flux directly through nAChR channels or indirectly via voltage-gated Ca2+ channels is relevant for nicotinic modulation of transmitter release, synaptic plasticity, as well as neuronal viability, differentiation, and migration.

a(CHEBI:"calcium(2+)", loc(GO:intracellular)) regulates bp(GO:"signal release") View Subject | View Object

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a(CHEBI:"calcium(2+)", loc(GO:intracellular)) regulates bp(MESH:"Neuronal Plasticity") View Subject | View Object

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a(CHEBI:"calcium(2+)", loc(GO:intracellular)) regulates bp(GO:"neuron migration") View Subject | View Object

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a(CHEBI:"calcium(2+)", loc(GO:intracellular)) regulates bp(GO:"neuron differentiation") View Subject | View Object

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Evidence 998316343e
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Third, nAChR-mediated GABA release can cause neuronal hyperpolarization, which in turn affects neuronal function via several mechanisms, including removal of inactivation of inward currents (89).

sec(a(CHEBI:"gamma-aminobutyric acid")) increases bp(GO:"hyperpolarization of postsynaptic membrane") View Subject | View Object

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p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") increases sec(a(CHEBI:"gamma-aminobutyric acid")) View Subject | View Object

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Evidence c3927f140d
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Other levels of regulation of dopaminergic transmission arise from alpha7 nAChRs located on cortical glutamatergic terminals; activation of these receptors increases glutamate release onto dopaminergic neurons in the VTA and, consequently, increases the their firing (344).

a(CHEBI:"glutamate(2-)", loc(MESH:"Dopaminergic Neurons")) increases bp(GO:"synaptic transmission, dopaminergic") View Subject | View Object

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act(p(HGNC:CHRNA7, loc(GO:"glutamatergic synapse"))) regulates bp(GO:"synaptic transmission, dopaminergic") View Subject | View Object

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act(p(HGNC:CHRNA7, loc(GO:"glutamatergic synapse"))) increases a(CHEBI:"glutamate(2-)", loc(MESH:"Dopaminergic Neurons")) View Subject | View Object

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Evidence 73a30c338a
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Of note is that in both of these catastrophic disorders, reduced nAChR activity/expression is accompanied by increased levels of kynurenic acid (KYNA), a tryptophan metabolite that in the brain is primarily produced and released by astrocytes (244, 419).

a(CHEBI:"kynurenic acid") negativeCorrelation act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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a(MESH:Astrocytes) increases a(CHEBI:"kynurenic acid") View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) negativeCorrelation a(CHEBI:"kynurenic acid") View Subject | View Object

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Evidence 1acd6769b0
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The neuroactive properties of KYNA have long been attributed to the inhibition of NMDA receptors (329). Electrophysiological studies, however, have demonstrated that physiologically relevant concentrations of KYNA block alpha7 nAChR activity noncompetitively and voltage independently (210).

a(CHEBI:"kynurenic acid") decreases act(p(HGNCGENEFAMILY:"Glutamate ionotropic receptor NMDA type subunits")) View Subject | View Object

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a(CHEBI:"kynurenic acid") decreases act(p(HGNC:CHRNA7)) View Subject | View Object

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Evidence 88d17d0600
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This constituted the first evidence that in the hippocampus endogenous levels of KYNA are sufficient to directly modulate the activity of alpha7 nAChRs, but not that of NMDA receptors (31).

a(CHEBI:"kynurenic acid") regulates act(p(HGNC:CHRNA7)) View Subject | View Object

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Hippocampus
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Evidence cf91e1af57
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Acting as an endogenous regulator of the alpha7 nAChR activity, astrocyte-derived KYNA can modulate synaptic transmission, synaptic plasticity, neuronal viability, and neuronal connectivity in different areas of the brain (Fig. 8).

a(CHEBI:"kynurenic acid") regulates act(p(HGNC:CHRNA7)) View Subject | View Object

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a(CHEBI:"kynurenic acid") regulates bp(MESH:"Neuronal Plasticity") View Subject | View Object

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a(CHEBI:"kynurenic acid") regulates bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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a(CHEBI:"kynurenic acid") regulates path(MESH:"Cell Survival") View Subject | View Object

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Evidence 524b6db7f6
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Not unlike snake toxins, conotoxins can disrupt multiple components of neurotransmission including voltage-gated Na+ and K+ channels in addition to nAChRs (132, 351).

a(MESH:Conotoxins) decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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a(MESH:Conotoxins) decreases act(p(HGNCGENEFAMILY:"Potassium voltage-gated channels")) View Subject | View Object

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a(MESH:Conotoxins) decreases act(a(MESH:"Voltage-Gated Sodium Channels")) View Subject | View Object

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Evidence 947763488d
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As illustrated in Figure 8, KYNA-induced reduction of extracellular dopamine levels can be explained by the inhibition of tonically active alpha7 nAChRs in the dopaminergic neurons within the VTA and/or in cortical glutamatergic terminals that synapse onto striatal neurons. VTA dopaminergic neurons represent the major dopaminergic input to the nucleus accumbens.

a(CHEBI:"kynurenic acid") decreases act(p(HGNC:CHRNA7)) View Subject | View Object

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Dopaminergic Neurons
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act(p(HGNC:CHRNA7)) increases a(CHEBI:dopamine, loc(GO:"extracellular region")) View Subject | View Object

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Dopaminergic Neurons
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Evidence 16575429dc
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Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273).

a(CHEBI:"kynurenic acid") decreases act(p(HGNC:CHRNA7)) View Subject | View Object

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Hippocampus
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bp(GO:cognition) association act(p(HGNC:CHRNA7)) View Subject | View Object

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Hippocampus
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bp(GO:cognition) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Hippocampus
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act(p(HGNC:CHRNA7)) association bp(GO:cognition) View Subject | View Object

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Hippocampus
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act(p(HGNC:CHRNA7)) association path(MESH:"Sensory Gating") View Subject | View Object

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Hippocampus
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path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:cognition) View Subject | View Object

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Hippocampus
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path(MESH:"Sensory Gating") association path(MESH:Schizophrenia) View Subject | View Object

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Hippocampus
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path(MESH:"Sensory Gating") association act(p(HGNC:CHRNA7)) View Subject | View Object

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Hippocampus
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path(MESH:Schizophrenia) association path(MESH:"Sensory Gating") View Subject | View Object

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Hippocampus
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Evidence c2ee34bcf5
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Mice with a null mutation in the gene that encodes KAT II became a unique tool to resolve this issue (31, 410, 516). Low levels of KYNA in these mutant mice lead to alpha7 nAChR disinhibition in hippocampal CA1 SR interneurons, thereby increasing the activity of GABAergic interneurons impinging onto CA1 pyramidal neurons (31)

a(CHEBI:"kynurenic acid") decreases act(p(MGI:Chrna7, loc(MESH:Interneurons))) View Subject | View Object

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CA1 Region, Hippocampal
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act(p(MGI:Chrna7, loc(MESH:Interneurons))) increases act(a(MESH:"GABAergic Neurons")) View Subject | View Object

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CA1 Region, Hippocampal
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Evidence bf550822aa
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Activation of alpha7 nAChRs is known to contribute to the regulation of extracellular dopamine levels in the rat striatum (81). Application via microdialysis of KYNA or alpha-BGT to the rat striatum significantly reduces the extracellular levels of dopamine, and the magnitude of the effect of either antagonist alone is comparable to that of both antagonists together (285).

a(CHEBI:"kynurenic acid") decreases a(CHEBI:dopamine, loc(GO:"extracellular region")) View Subject | View Object

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Corpus Striatum
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a(HBP:"alpha-Bungarotoxin") decreases a(CHEBI:dopamine, loc(GO:"extracellular region")) View Subject | View Object

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Corpus Striatum
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act(p(HGNC:CHRNA7)) regulates a(CHEBI:dopamine, loc(GO:"extracellular region")) View Subject | View Object

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Corpus Striatum
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Evidence e9aa0bf41f
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Surprisingly, however, activation of nAChRs by galantamine or physostigmine was insensitive to blockade by competitive nAChR antagonists, was detected even when the receptors were desensitized by high agonist concentrations, and was inhibited by the monoclonal antibody FK1 (350, 370, 372, 413, 428, 429).

a(CHEBI:"nicotinic antagonist") causesNoChange act(a(CHEBI:galanthamine)) View Subject | View Object

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a(CHEBI:"nicotinic antagonist") causesNoChange act(a(CHEBI:physostigmine)) View Subject | View Object

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a(CHEBI:galanthamine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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a(CHEBI:physostigmine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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a(HBP:"FK1 antibody") decreases act(a(CHEBI:galanthamine)) View Subject | View Object

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a(HBP:"FK1 antibody") decreases act(a(CHEBI:physostigmine)) View Subject | View Object

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Evidence 39107c41e8
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Thus inhibitors of proteasome function block endoplasmic reticulum-associated degradation of unassembled AChR subunits, which in turn increases the availability of subunits for assembly into mature receptors that are trafficked to the cell surface.

a(CHEBI:"proteasome inhibitor") decreases deg(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits", loc(GO:"endoplasmic reticulum"))) View Subject | View Object

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Evidence 6fb19ba526
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The metabotropic receptors are second messenger, G protein-coupled seven-transmembrane proteins. They are classically defined as being activated by muscarine, a toxin from the mushroom Amanita muscaria, and inhibited by atropine, a toxin from Atropa belladonna, a member of the nightshade family. Both toxins cross the blood-brain barrier poorly and were discovered primarily from their influences on postganglionic parasympathetic nervous system functions. Activation of muscarinic AChRs is relatively slow (milliseconds to seconds) and, depending on the subtypes present (M1- M5), they directly alter cellular homeostasis of phospholipase C, inositol trisphosphate, cAMP, and free calcium.

a(CHEBI:Muscarine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic")) View Subject | View Object

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a(CHEBI:atropine) decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic")) View Subject | View Object

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a(TAXONOMY:33113) increases a(CHEBI:atropine) View Subject | View Object

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a(TAXONOMY:41956) increases a(CHEBI:Muscarine) View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic")) regulates p(FPLX:PLC) View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic")) regulates a(CHEBI:"3',5'-cyclic AMP") View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic")) regulates a(CHEBI:"myo-inositol trisphosphate") View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic")) regulates a(CHEBI:"calcium ion") View Subject | View Object

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Evidence fdfc6e1fa4
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Acetylcholine receptors (AChRs), like many other ligand-activated neurotransmitter receptors, consist of two major subtypes: the metabotropic muscarinic receptors and the ionotropic nicotinic receptors. Both share the property of being activated by the endogenous neurotransmitter acetylcholine (ACh), and they are expressed by both neuronal and nonneuronal cells throughout the body (8, 113, 142, 184).

a(CHEBI:acetylcholine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic")) View Subject | View Object

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a(CHEBI:acetylcholine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Evidence fc92fe1407
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From the time of its discovery in 1914 by Henry H. Dale (109) and Otto Loewi (283) (the two shared the Nobel Prize in Physiology and Medicine in 1936) as an agent that decreases heart rate, ACh was recognized as an endogenous signaling compound, synthesized from choline and acetyl-CoA, through the action of choline acetyltransferase, that alters cell function.

a(CHEBI:acetylcholine) decreases path(MESH:"Heart Rate") View Subject | View Object

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a(CHEBI:acetylcholine) association bp(GO:signaling) View Subject | View Object

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bp(GO:signaling) association a(CHEBI:acetylcholine) View Subject | View Object

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act(p(HGNC:CHAT)) directlyIncreases rxn(reactants(a(CHEBI:"acetyl-CoA"), a(CHEBI:choline)), products(a(CHEBI:acetylcholine))) View Subject | View Object

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Evidence 88ccdec02a
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Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).

a(CHEBI:anandamide) association p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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a(CHEBI:anandamide) association p(HGNC:CNR1) View Subject | View Object

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a(CHEBI:anandamide) association p(HGNC:CNR2) View Subject | View Object

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a(CHEBI:anandamide) association complex(GO:"voltage-gated calcium channel complex") View Subject | View Object

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a(CHEBI:anandamide) association p(HGNCGENEFAMILY:"Potassium voltage-gated channels") View Subject | View Object

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a(CHEBI:anandamide) association a(MESH:"Receptors, Serotonin") View Subject | View Object

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a(CHEBI:anandamide) association p(HGNCGENEFAMILY:"Glutamate ionotropic receptor kainate type subunits") View Subject | View Object

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a(CHEBI:anandamide) decreases act(p(HGNC:CHRNA7)) View Subject | View Object

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a(CHEBI:anandamide) decreases act(p(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

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a(MESH:"Receptors, Serotonin") association a(CHEBI:anandamide) View Subject | View Object

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complex(GO:"voltage-gated calcium channel complex") association a(CHEBI:anandamide) View Subject | View Object

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p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") association a(CHEBI:anandamide) View Subject | View Object

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p(HGNC:CNR1) association a(CHEBI:anandamide) View Subject | View Object

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p(HGNC:CNR2) association a(CHEBI:anandamide) View Subject | View Object

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p(HGNCGENEFAMILY:"Glutamate ionotropic receptor kainate type subunits") association a(CHEBI:anandamide) View Subject | View Object

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p(HGNCGENEFAMILY:"Potassium voltage-gated channels") association a(CHEBI:anandamide) View Subject | View Object

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Evidence 8564582c7a
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Furthermore, pharmacological dissection of nicotine’s influence on cell cycle progression, apoptosis, and differentiation (43) indicate that alpha7 nAChRs expressed in keratynocytes are important. Other receptors are clearly involved in this process, since atropine, a muscarinic and sometimes nAChR inhibitor (531, 532), reduces cell adhesion through decreasing desmoligein expression.

a(CHEBI:atropine) decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic")) View Subject | View Object

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Keratinocytes
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a(CHEBI:atropine) decreases bp(GO:"cell adhesion") View Subject | View Object

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Keratinocytes
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p(HGNC:CHRNA7) regulates bp(GO:"cell cycle") View Subject | View Object

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Keratinocytes
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Evidence 9a4535cbd9
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Finally, bupropion (16, 294, 433) and UCI-30002 (514) are examples of synthetic compounds that act as noncompetitive inhibitors of different nAChRs, including those made up of the subunits alpha7, alpha4beta2, or alpha3beta4. Both compounds effectively decrease nicotine self-administration in rats (280, 514). Bupropion is presently approved as an adjunct therapy for smoking cessation.

a(CHEBI:bupropion) decreases act(p(HGNC:CHRNA7)) View Subject | View Object

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a(CHEBI:bupropion) decreases act(p(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

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a(CHEBI:bupropion) decreases act(p(HBP:"alpha-3 beta-4 nAChR")) View Subject | View Object

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a(CHEBI:bupropion) association path(MESH:"Smoking Cessation") View Subject | View Object

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a(MESH:"N-(1,2,3,4-tetrahydro-1-naphthyl)-4-nitroaniline") decreases act(p(HGNC:CHRNA7)) View Subject | View Object

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a(MESH:"N-(1,2,3,4-tetrahydro-1-naphthyl)-4-nitroaniline") decreases act(p(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

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a(MESH:"N-(1,2,3,4-tetrahydro-1-naphthyl)-4-nitroaniline") decreases act(p(HBP:"alpha-3 beta-4 nAChR")) View Subject | View Object

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path(MESH:"Smoking Cessation") association a(CHEBI:bupropion) View Subject | View Object

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Evidence ea6c09fc0b
JSON

For instance, studies carried out in PC12 cells demonstrated that codeine, a drug with no significant effect on ChE, can activate nicotinic single-channel currents and that this nicotinic agonist effect is sensitive to inhibition by FK1 while unaffected by classical nAChR antagonists (450).

a(CHEBI:codeine) causesNoChange a(MESH:Cholinesterases) View Subject | View Object

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PC12 Cells
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a(CHEBI:codeine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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PC12 Cells
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a(HBP:"FK1 antibody") decreases a(CHEBI:codeine) View Subject | View Object

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PC12 Cells
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Evidence 6c2901642a
JSON

Drugs currently approved to treat mild-to-moderate AD, including galantamine, donepezil, and rivastigmine, all inhibit AChE, the enzyme that hydrolyzes ACh (462).

a(CHEBI:donepezil) decreases p(HGNC:ACHE) View Subject | View Object

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a(CHEBI:galanthamine) decreases p(HGNC:ACHE) View Subject | View Object

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a(CHEBI:rivastigmine) decreases p(HGNC:ACHE) View Subject | View Object

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Evidence fa81dc1832
JSON

Studies from the early 1980s provided evidence that the cholinesterase (ChE) inhibitor physostigmine could interact directly with nAChRs at the frog neuromuscular junction and induce nicotinic single-channel currents (428, 429).

a(CHEBI:physostigmine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits", loc(MESH:"Neuromuscular Junction"))) View Subject | View Object

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Evidence 756e7610fd
JSON

Parkinson’s disease (PD) is characterized by selective damage to dopaminergic nigrostriatal neurons and is clinically revealed by motor deficits, including rigidity, tremor, and bradykinesia. Dopamine replacement therapy (usually with L-dopa) is the most common treatment, although this drug loses efficacy over time.

a(CHEBI:dopamine) decreases path(MESH:"Parkinson Disease") View Subject | View Object

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Dopaminergic Neurons
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path(MESH:"Muscle Rigidity") positiveCorrelation path(MESH:"Parkinson Disease") View Subject | View Object

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Dopaminergic Neurons
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path(MESH:"Parkinson Disease") positiveCorrelation path(MESH:Tremor) View Subject | View Object

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Dopaminergic Neurons
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path(MESH:"Parkinson Disease") positiveCorrelation path(MESH:Hypokinesia) View Subject | View Object

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Dopaminergic Neurons
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path(MESH:"Parkinson Disease") positiveCorrelation path(MESH:"Muscle Rigidity") View Subject | View Object

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Dopaminergic Neurons
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path(MESH:Hypokinesia) positiveCorrelation path(MESH:"Parkinson Disease") View Subject | View Object

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Dopaminergic Neurons
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path(MESH:Tremor) positiveCorrelation path(MESH:"Parkinson Disease") View Subject | View Object

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Dopaminergic Neurons
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Evidence e33e8e6f0e
JSON

An alternative means to increase nicotinic functions in the brain is to sensitize the nAChRs to activation by the endogenous agonist(s) using the so-called nicotinic allosteric potentiating ligands (APLs), which include drugs such as physostigmine and galantamine, a drug currently approved for the treatment of AD.

a(CHEBI:galanthamine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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a(CHEBI:physostigmine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Evidence 354d033e29
JSON

In the early 1990s, galantamine, an alkaloid originally extracted from the bulbs and flowers of the wild Caucasian snowdrop Galanthus nivalis and other related Amaryllidacea species, was found to act like physostigmine on muscle and neuronal nAChRs (370, 372).

a(CHEBI:galanthamine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Evidence 78c7e4cda5
JSON

The nicotinic APL action of galantamine appears to be an important determinant of its clinical effectiveness (reviewed in Refs. 98, 291, 371). Acting primarily as a nicotinic APL, galantamine improves synaptic transmission and decreases neurodegeneration, two effects essential for its cognitive-enhancing properties (40, 108, 241, 409, 521).

a(CHEBI:galanthamine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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a(CHEBI:galanthamine) decreases path(HBP:Neurodegeneration) View Subject | View Object

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a(CHEBI:galanthamine) increases bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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Evidence fff3ed6ee1
JSON

In the normal brain, 70% of KYNA formation is catalyzed by KAT II, one of the three cerebral KATs (199, 200). Systemic treatment of rats and mice with kynurenine leads to an elevation of brain levels of several neuroactive intermediates, including KYNA, the free radical generator 3-hydroxykynurenine, and the excitotoxic quinolinic acid (419).

a(CHEBI:kynurenine) increases a(CHEBI:"kynurenic acid") View Subject | View Object

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a(CHEBI:kynurenine) increases a(CHEBI:"3-hydroxykynurenine") View Subject | View Object

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a(CHEBI:kynurenine) increases a(CHEBI:"quinolinic acid") View Subject | View Object

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act(p(HGNC:AADAT), ma(cat)) increases a(CHEBI:"kynurenic acid") View Subject | View Object

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Evidence a6a3cf067c
JSON

The other subtype of AChR is the fast ionotropic cationic nicotinic receptor channel (nAChR). These receptors are sensitive to activation by nicotine and have ion channels whose activity is induced in the micro- to submicrosecond range.

a(CHEBI:nicotine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Evidence 8aadd21846
JSON

Also, the continuous exposure of cells to nicotine increases nAChR surface expression by reducing degradation of the intracellular pool of receptors (367, 394).

a(CHEBI:nicotine) decreases deg(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits", loc(GO:"endoplasmic reticulum"))) View Subject | View Object

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Evidence 0f710bc18a
JSON

In the smoker’s brain, upregulation can increase high-affinity nicotine binding by nearly fourfold relative to age- and gender-matched controls that have not been exposed to nicotine (373, 421). The mechanism by which nicotine increases the total number of high-affinity nAChRs, though poorly defined, is highly conserved among species.

a(CHEBI:nicotine) increases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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Evidence 2fae159ee2
JSON

Mechanistically, nicotine, acting through nAChRs, decreases keratinocyte migration (188, 189) and modifies the activity of PI3K/Akt, ERK, MEK, and JAK signaling pathways.

a(CHEBI:nicotine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Keratinocytes
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act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) decreases bp(GO:"keratinocyte migration") View Subject | View Object

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Keratinocytes
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act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) regulates bp(GO:"phosphatidylinositol 3-kinase signaling") View Subject | View Object

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Keratinocytes
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act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) regulates bp(GO:"ERK1 and ERK2 cascade") View Subject | View Object

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Keratinocytes
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act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) regulates bp(GO:"receptor signaling pathway via JAK-STAT") View Subject | View Object

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Keratinocytes
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Evidence ea9f822ef5
JSON

First, age-related nAChR subunit expression decline was observed in both strains, and this was dominated by diminished alpha4 nAChR expression. Second, long-term (12 mo) oral nicotine failed to reduce the age-related decline in the number of neurons expressing alpha4 nAChR subunits, although the neurons that remained exhibited larger processes with more varicosities than age-matched controls (165, 396). Acute nicotine treatment (alpha6 wk of oral nicotine) of aged mice had no measurable influence on nAChR expression, neuronal viability, or dendritic complexity (e.g., Ref. 396)

a(CHEBI:nicotine) causesNoChange p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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a(CHEBI:nicotine) causesNoChange p(MGI:Chrna4) View Subject | View Object

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path(MESH:Aging) decreases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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path(MESH:Aging) decreases p(MGI:Chrna4) View Subject | View Object

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Evidence 8325d11f72
JSON

Nicotine is perhaps the most addictive drug that is widely used; 95% or more of its users with a strong desire to stop using it relapse within 1 yr (47, 203). Chronic nicotine use and the phenotypes of addiction are closely associated in humans and other animals with concurrent physiological changes in nAChR function and expression

a(CHEBI:nicotine) regulates p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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a(CHEBI:nicotine) regulates act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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a(CHEBI:nicotine) increases path(MESH:"Behavior, Addictive") View Subject | View Object

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Evidence 8defb0407e
JSON

One insect has escaped the ill effects of nicotine, Manduca sextans or the tobacco horn worm. While nicotine binds the nAChR to activate and subsequently desensitize it, this insect eats the tobacco plant without ill effects. Manduca exhibits two adaptations to tolerate the effects of nicotine. The first is altered nAChR amino acid sequences that limit the affinity of nicotine for the nAChR (136). The second is the development of the functional equivalent to a blood-brain barrier.

a(CHEBI:nicotine) causesNoChange a(MESH:Manduca) View Subject | View Object

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a(MESH:Manduca) association bp(GO:"establishment of blood-brain barrier") View Subject | View Object

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bp(GO:"establishment of blood-brain barrier") association a(MESH:Manduca) View Subject | View Object

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p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") decreases bp(GO:"response to nicotine") View Subject | View Object

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Evidence 9de0dc07e2
JSON

Metabolic degradation of nicotine and rapid clearance is a mechanism that protects neurons from greater nicotine concentrations, since nicotine readily crosses the mammalian blood-brain barrier and accumulates in the lipophilic brain environment to concentrations that may exceed plasma concentrations by one order of magnitude. Nevertheless, neurotoxicity to nicotine is not uncommon, as attested to by the recent increase in hospital emergency room visits by smokers who concurrently use the transdermal nicotine patch (503).

a(CHEBI:nicotine) association path(HBP:neurotoxicity) View Subject | View Object

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a(MESH:Neurons) increases deg(a(CHEBI:nicotine)) View Subject | View Object

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path(HBP:neurotoxicity) association a(CHEBI:nicotine) View Subject | View Object

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Evidence d972ccfbc3
JSON

The receptor that exhibits the greatest upregulation when exposed to nicotine is the alpha4beta2 nAChR. Receptors assembled from this subunit combination form the highaffinity nicotine binding site (151, 215) and account for the vast majority of upregulated sites in the brain of smokers (55).

a(CHEBI:nicotine) increases p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

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a(CHEBI:nicotine) increases complex(a(CHEBI:nicotine), p(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

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Evidence 5a07fdb6ba
JSON

transfection of cells with the beta4 and alpha2 nAChR subunits or expression of these in Xenopus oocytes leads to high-affinity nicotine-binding receptors that upregulate in response to prolonged exposure to nicotine (113, 184, 215).

a(CHEBI:nicotine) increases p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

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Evidence 3884521f7b
JSON

On the other hand, when alpha4beta2 nAChRs are activated, both SR and SLM interneurons are inhibited, resulting in disinhibition of dendritic areas innervated by both neuron types.

act(a(HBP:"alpha-4 beta-2 nAChR")) decreases act(a(MESH:Interneurons)) View Subject | View Object

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Uberon
hippocampus stratum lacunosum moleculare
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Evidence f582398308
JSON

In particular, repeated self-administration produces the upregulation of high-affinity (alpha4beta2) nAChR expression, reduces receptor function due to desensitization and, in most cases, imparts developmental tolerance. Additional changes imposed by nicotine abuse range from reinforcement to physical discomfort associated with withdrawal including craving, anxiety, and a multitude of other less than desirable sensations of autonomic dysfunction when use is stopped.

a(CHEBI:nicotine) increases p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

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a(CHEBI:nicotine) decreases act(p(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

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a(CHEBI:nicotine) increases path(MESH:Craving) View Subject | View Object

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a(CHEBI:nicotine) increases path(MESH:Anxiety) View Subject | View Object

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Evidence 021b44f1d4
JSON

For instance, prolonged exposure of HEK293 cells to saturating nicotine concentrations increased by 6- and 1.5-fold, respectively, the expression of alpha3beta2 and alpha3beta4 nAChRs.Similarly, while alpha4beta2 nAChRs upregulate strongly, alpha4beta4 nAChRs upregulate poorly in response to continuous exposure to nicotine.

a(CHEBI:nicotine) increases a(HBP:"alpha-3 beta-2 nAChR") View Subject | View Object

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Experimental Factor Ontology (EFO)
HEK293
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a(CHEBI:nicotine) increases a(HBP:"alpha-3 beta-4 nAChR") View Subject | View Object

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Experimental Factor Ontology (EFO)
HEK293
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Evidence 4d87ec13af
JSON

Prolonged treatment of rodents and monkeys with nicotine downregulates the expression of alpha6beta3-containing nAChRs in the brain (257, 311, 332). However, in heterologous culture systems, nicotine appears to upregulate the expression of receptors assembled from alpha4/alpha6/beta2/beta3 input cDNA (363), and this may depend on numerous factors including ligand concentrations (483).

a(CHEBI:nicotine) decreases complex(p(HGNC:CHRNA6), p(HGNC:CHRNB3)) View Subject | View Object

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Brain
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composite(a(CHEBI:nicotine), g(HGNC:CHRNA4), g(HGNC:CHRNA6), g(HGNC:CHRNB2), g(HGNC:CHRNB3)) increases composite(p(HGNC:CHRNA4), p(HGNC:CHRNA6), p(HGNC:CHRNB2), p(HGNC:CHRNB3)) View Subject | View Object

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Evidence fc8e1b4d62
JSON

An ever-growing body of evidence indicates that in CNS and parasympathetic nervous system neurons and in heterologous systems expressing specific nAChR subtypes, nicotine stimulates several Ca2+-dependent kinases, including PI3K, protein kinase C (PKC), protein kinase A (PKA), calmodulin-dependent protein kinase II (CAM kinase II), and extracellular signal-regulated kinases (ERKs; Refs. 108, 112, 146, 318, 469).

a(CHEBI:nicotine) increases act(p(FPLX:PI3K)) View Subject | View Object

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Central Nervous System
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Parasympathetic Nervous System
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a(CHEBI:nicotine) increases act(p(FPLX:PKA)) View Subject | View Object

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Central Nervous System
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Parasympathetic Nervous System
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a(CHEBI:nicotine) increases act(p(FPLX:PKC)) View Subject | View Object

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Central Nervous System
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Parasympathetic Nervous System
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a(CHEBI:nicotine) increases act(p(FPLX:"CAMK2_complex")) View Subject | View Object

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Central Nervous System
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Parasympathetic Nervous System
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Evidence b97360c451
JSON

Downstream from the nicotine-stimulated kinases, a number of transcription factors have been shown to be activated. Among these factors are the cAMP response element binding protein (CREB) and the activating transcription factor 2 (ATF-2) in PC12 cells (211, 337, 460), the Ets-like transcription factor Elk-1 in the rat hippocampus (349), and the signal transducer and activator of transcription (STAT3) in macrophages and skin cells (114, 354).

act(a(CHEBI:nicotine)) increases act(p(FPLX:CREB)) View Subject | View Object

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PC12 Cells
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act(a(CHEBI:nicotine)) increases act(p(HGNC:ATF2)) View Subject | View Object

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PC12 Cells
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act(a(CHEBI:nicotine)) increases act(p(RGD:Elk1)) View Subject | View Object

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Hippocampus
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act(a(CHEBI:nicotine)) increases act(p(HGNC:STAT3)) View Subject | View Object

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Macrophages
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Skin
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Evidence b576854193
JSON

Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below.

act(a(CHEBI:nicotine)) association a(MESH:Skin) View Subject | View Object

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Skin
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a(MESH:Skin) association act(a(CHEBI:nicotine)) View Subject | View Object

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Skin
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bp(GO:"ERK1 and ERK2 cascade") increases act(a(CHEBI:nicotine)) View Subject | View Object

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Skin
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bp(GO:"receptor signaling pathway via JAK-STAT") increases act(a(CHEBI:nicotine)) View Subject | View Object

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Skin
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bp(MESH:"Neuronal Plasticity") association act(p(FPLX:CREB)) View Subject | View Object

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bp(MESH:"Neuronal Plasticity") association act(p(HGNC:MAPK1)) View Subject | View Object

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act(p(FPLX:CREB)) association bp(MESH:"Neuronal Plasticity") View Subject | View Object

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act(p(FPLX:CREB)) association path(MESH:"Tobacco Use Disorder") View Subject | View Object

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act(p(HGNC:MAPK1)) association bp(MESH:"Neuronal Plasticity") View Subject | View Object

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act(p(HGNC:MAPK1)) association path(MESH:"Tobacco Use Disorder") View Subject | View Object

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path(MESH:"Tobacco Use Disorder") association act(p(HGNC:MAPK1)) View Subject | View Object

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path(MESH:"Tobacco Use Disorder") association act(p(FPLX:CREB)) View Subject | View Object

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Evidence 68b8bd71c9
JSON

Modulation by nicotine of inflammatory responses in the intestines is much better reported. Early studies found that patients with ulcerative colitis who stopped smoking tobacco developed the disease or exhibited more severe disease progression, which was ameliorated by either returning to smoking (58, 401, 466), or, in some cases, administering nicotine through transdermal patches (313).In contrast, patients with Crohn’s disease experience much more severe disease when smoking (401).

act(a(CHEBI:nicotine)) regulates bp(GO:"inflammatory response") View Subject | View Object

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Intestines
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a(CHEBI:nicotine) decreases path(MESH:"Colitis, Ulcerative") View Subject | View Object

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Intestines
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path(MESH:"Tobacco Use Disorder") decreases path(MESH:"Colitis, Ulcerative") View Subject | View Object

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MeSH
Intestines
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path(MESH:"Tobacco Use Disorder") increases path(MESH:"Crohn Disease") View Subject | View Object

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Intestines
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Evidence 959cdca00a
JSON

Notably, mice with a null mutation in the gene that encodes the alpha5 nAChR subunit exhibit enhanced sensitivity to induction of inflammatory bowel disease relative to controls (353). Despite increased sensitivity to disease initiation, administration of transdermal nicotine remains effective in attenuating the disease process. Therefore, again nicotine appears to impact on inflammatory processes with considerable specificity and tissue dependency.

a(CHEBI:nicotine) decreases path(MESH:"Inflammatory Bowel Diseases") View Subject | View Object

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p(HGNC:CHRNA5) decreases path(MESH:"Inflammatory Bowel Diseases") View Subject | View Object

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Evidence 8ec4876e4d
JSON

Notably, nicotine pretreatment of rat adipocytes (279) reduces the release of TNF-alpha as well as free fatty acids and the adipokine adiponectin (whose function is not known, although its levels change in metabolic syndrome).

a(CHEBI:nicotine) decreases sec(p(HGNC:TNF)) View Subject | View Object

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Adipocytes
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Evidence 870ba52827
JSON

Mice are particularly well-defined for their strain-specific complex genetic traits related to the effects of nicotine (105, 302) and morphological variations in the brain (e.g., Refs. 166, 167, 169).

act(a(CHEBI:nicotine)) association path(MESH:"Genetic Variation") View Subject | View Object

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path(MESH:"Genetic Variation") association act(a(CHEBI:nicotine)) View Subject | View Object

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Evidence 4e16b305ae
JSON

In human trials, nicotine showed little efficacy in ameliorating AD symptoms (437). However, treatment was initiated after diagnosis of symptoms, and there is both epidemiological data and direct evidence from animal models that this is too late (106, 346, 396).

a(CHEBI:nicotine) causesNoChange path(MESH:"Alzheimer Disease") View Subject | View Object

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Evidence 5568688078
JSON

More direct evidence of the protective effects of nicotine in this disease process comes from studies in primates, where oral nicotine reduces the nigrostriatal neuronal loss observed in chemically induced PD (384, 385).

a(CHEBI:nicotine) decreases bp(GO:"neuron death") View Subject | View Object

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Parkinson Disease
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Evidence bb99b8aaa9
JSON

However, in rodent and nonprimate animal models, nicotine has been shown to enhance striatal dopamine release and to prevent toxin-induced degeneration of dopaminergic neurons (384, 385).

a(CHEBI:nicotine) decreases bp(GO:"neuron death") View Subject | View Object

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Corpus Striatum
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a(CHEBI:nicotine) increases sec(a(CHEBI:dopamine)) View Subject | View Object

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Corpus Striatum
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Evidence f1a3ad363f
JSON

A principle component of genetic analysis of the contribution of alpha7 and alpha4beta2 nAChRs to the effects of nicotine was reported 15 years ago. The number of alpha-BGT binding sites (presumably alpha7 nAChRs) was shown to be highly correlated with sensitivity to nicotinic-induced seizures (105, 301, 303).

a(CHEBI:nicotine) association act(p(HGNC:CHRNA7)) View Subject | View Object

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Seizures
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act(p(HGNC:CHRNA7)) association a(CHEBI:nicotine) View Subject | View Object

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Seizures
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Evidence 75b94cae5c
JSON

The concept that beta2-containing nAChRs are involved in the reinforcing effects of nicotine was supported by the findings that these mice lacked the high-affinity nicotine binding site, exhibited poor nicotine self-administration, and failed to develop behaviors related to reinforcement (378). The demonstration that these mice developed symptoms of the nicotine withdrawal syndrome similar to those observed in wild-type mice led to the conclusion that beta2-containing nAChRs do not contribute to the physical dependence on nicotine (57).

a(CHEBI:nicotine) association a(HBP:"beta-2-containing nAChR") View Subject | View Object

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a(HBP:"beta-2-containing nAChR") association a(CHEBI:nicotine) View Subject | View Object

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a(HBP:"beta-2-containing nAChR") causesNoChange act(a(CHEBI:nicotine)) View Subject | View Object

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Evidence 90b6bbcb83
JSON

In summary, while nicotine-induced upregulation requires at least the beta2 nAChR subunit, development of tolerance to nicotine requires neither the beta2 nor the alpha7 nAChR subunit; instead, it appears to be modulated by a beta4-containing nAChR and to require an alpha4-containing nAChR.

a(HBP:"alpha-4-containing nAChR") association path(MESH:"Drug Tolerance") View Subject | View Object

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p(HGNC:CHRNB4) association path(MESH:"Drug Tolerance") View Subject | View Object

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path(MESH:"Drug Tolerance") association p(HGNC:CHRNB4) View Subject | View Object

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path(MESH:"Drug Tolerance") association a(HBP:"alpha-4-containing nAChR") View Subject | View Object

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Evidence 1931e37022
JSON

The second was the discovery of alpha-bungarotoxin (alpha-BGT), a component of krait snake venom that binds muscle-type nAChRs with near covalent affinity to inhibit their function and promote debilitating paralysis at the neuromuscular junction (6, 50, 149, 264).

a(HBP:"alpha-Bungarotoxin") decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Evidence 5594c9b28c
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The most valuable of these toxins to researchers proved to be alpha-BGT from the snake Bungarus multicinctus. Because this toxin binds to the muscle nAChR with great specificity and a near-covalent affinity, it was an invaluable tool in the purification of the first nAChRs (discussed above).

a(HBP:"alpha-Bungarotoxin") increases complex(a(HBP:"alpha-Bungarotoxin"), p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Evidence 5b79de8302
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However, this appealing scenario is complicated by recent findings that beta-amyloid peptides directly modify alpha7 nAChR function (242, 278).

a(HBP:"amyloid-beta oligomers") regulates act(p(HGNC:CHRNA7)) View Subject | View Object

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Evidence fabeaebc88
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In contrast, the NMDA receptor antagonist 7-chloro-KYNA has no significant ef- fect on the extracellular levels of dopamine in the rat striatum (391).

a(MESH:"7-chlorothiokynurenic acid") causesNoChange a(CHEBI:dopamine, loc(GO:"extracellular region")) View Subject | View Object

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Corpus Striatum
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Evidence e4a4fef4a6
JSON

NSAIDs [e.g., drugs such as ibuprofen and NS398 (celecoxib or Celebrex)] antagonize to varying degrees two related cyclooxygenase (Cox) enzymes, Cox1 and Cox2 (also termed, prostaglandin-endoperoxide synthase 2), that are rate-limiting in converting arachidonic acid to prostaglandin H2, a precursor to many additional prostaglandins (for review, see Ref. 436).

a(MESH:"Anti-Inflammatory Agents, Non-Steroidal") decreases act(p(HGNC:PTGS1)) View Subject | View Object

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a(MESH:"Anti-Inflammatory Agents, Non-Steroidal") decreases act(p(HGNC:PTGS2)) View Subject | View Object

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act(p(HGNC:PTGS1)) increases a(CHEBI:"prostaglandin H2") View Subject | View Object

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act(p(HGNC:PTGS2)) increases a(CHEBI:"prostaglandin H2") View Subject | View Object

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Evidence ebefd5709b
JSON

For example, Loring and colleagues (458) compared the relative expression of alpah4beta2 versus alpha7 nAChRs transfected into five different cell lines (GH4C1, SH-EP1, CV1, SN-56, and CHOCAR). Each cell line expressed appropriate mRNAs (indicating successful transfection); however, the relative levels of expression of each receptor subtype varied significantly among the various cell lines.

a(MESH:"Cell Line") regulates r(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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Evidence cfb956e6f0
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All cell lines appeared to produce alpha4beta2 nAChRs, although at considerably variable levels relative to each other. Therefore, cell and receptor identity combine to collectively determine the efficiency of nAChR expression on the cell surface.

a(MESH:"Cell Line") regulates complex(p(HGNC:CHRNA4), p(HGNC:CHRNB2)) View Subject | View Object

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Evidence 31b2ab0ac4
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In fact, as described above, AChE inhibitors do not affect alpha7 nAChR-mediated synaptic transmission evoked by low-frequency stimulation of cholinergic fibers in chick ciliary ganglia (522).

a(MESH:"Cholinesterase Inhibitors") causesNoChange act(p(HGNC:CHRNA7)) View Subject | View Object

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Evidence d9dbdda85b
JSON

The first was the finding that the electric organ of a fish that produces an electric pulse to stun its prey, such as Torpedo, expresses nAChRs at densities that approach a crystalline array (245, 438). This provided an unprecedented source of starting material for receptor purification since nAChRs comprise 40% of the protein from this organ.

a(MESH:"Electric Fish") association p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") association a(MESH:"Electric Fish") View Subject | View Object

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Evidence bc3c535341
JSON

Another significant assembly checkpoint to ensure only correctly assembled nAChRs are transported to the cell surface is the endoplasmic reticulum. Most nAChRs are not constitutively sent to lysosomes. Instead, they are retained in intracellular pools that range from 65 to 85% of the total receptor number in a cell (147, 359, 397, 496).

a(MESH:"Endoplasmic Reticulum") regulates bp(HBP:"nAChR assembly") View Subject | View Object

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Evidence b305aba908
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In fact, 80% of the synthesized subunits appear to improperly assemble or never leave the endoplasmic reticulum where they are then degraded (485). The process of retaining subunits and possibly fully assembled receptors and then degrading them may be an important component of regulating receptor number.

a(MESH:"Endoplasmic Reticulum") regulates p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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a(MESH:"Endoplasmic Reticulum") increases deg(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits", loc(GO:"endoplasmic reticulum"))) View Subject | View Object

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Evidence 6b50c8d650
JSON

Neuronal nAChRs are not expressed exclusively in neurons. Instead, they are expressed by multiple cell types of diverse origins and functions including glia (165, 167, 425), keratinocytes (44, 86, 95, 426), endothelial cells (290, 495), and multiple cell types of the digestive system, lungs, and immune system (e.g., Refs. 95, 309, 492, 495).

a(MESH:"Endothelial Cells") increases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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a(MESH:Keratinocytes) increases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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a(MESH:Neuroglia) increases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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Evidence f5a34edd8e
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For instance, substantial strain-specific variability in nAChR expression has been observed in the striatum (34), retina (227), cerebellum (471), and dorsal hippocampus (164, 165, 167, 169) of mice.

a(MESH:"Mice, Inbred Strains") association p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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Cerebellum
MeSH
Corpus Striatum
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Hippocampus
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Retina
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p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") association a(MESH:"Mice, Inbred Strains") View Subject | View Object

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Cerebellum
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Corpus Striatum
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Hippocampus
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Retina
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Evidence 29372c2ab9
JSON

These results suggest that mouse strains of different genetic backgrounds undergo dissimilar age-related changes in the expression of nAChR subunits.

a(MESH:"Mice, Inbred Strains") association p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") association a(MESH:"Mice, Inbred Strains") View Subject | View Object

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Evidence d6a5531b28
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Activation of alpha7 nAChRs in somatodendritic and preterminal/ terminal areas of interneurons in various strata of the CA1 region and in the dentate gyrus facilitates spontaneous quantal release of GABA (14, 25). Glutamate release from mossy fibers onto CA3 pyramidal neurons is also modulated by alpha7 nAChRs present in the mossy fiber terminals (190).

a(MESH:"Mossy Fibers, Hippocampal") increases a(CHEBI:"glutamate(2-)", loc(MESH:"Pyramidal Cells")) View Subject | View Object

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CA1 Region, Hippocampal
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p(HGNC:CHRNA7, loc(MESH:"Mossy Fibers, Hippocampal")) regulates a(CHEBI:"glutamate(2-)", loc(MESH:"Pyramidal Cells")) View Subject | View Object

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CA1 Region, Hippocampal
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act(p(HGNC:CHRNA7)) increases sec(a(CHEBI:"gamma-aminobutyric acid")) View Subject | View Object

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CA1 Region, Hippocampal
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Evidence 9b57dc76d1
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Strain-dependent variations in nAChR density in regions of the rat brain have also been reported.

a(MESH:"Rats, Inbred Strains") association p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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Brain
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p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") association a(MESH:"Rats, Inbred Strains") View Subject | View Object

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Brain
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Evidence d0ee78468b
JSON

For instance, the alpha3 nAChR transcript generally dominates in the prenatal brain or in injured neurons, whereas its expression tends to be downregulated in the adult or healthy neuron, and alpha4 transcription is increased.

a(MESH:Adult) decreases r(HGNC:CHRNA3) View Subject | View Object

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a(MESH:Adult) increases r(HGNC:CHRNA4) View Subject | View Object

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a(MESH:Fetus) increases r(HGNC:CHRNA3, loc(MESH:Brain)) View Subject | View Object

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a(MESH:Neurons) decreases r(HGNC:CHRNA3) View Subject | View Object

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a(MESH:Neurons) increases r(HGNC:CHRNA4) View Subject | View Object

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path(MESH:"Trauma, Nervous System") increases r(HGNC:CHRNA3, loc(MESH:Brain)) View Subject | View Object

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Evidence cf8deb1d37
JSON

This is also true of alpha3, alpha4, beta2, and beta4 nAChR subunits, which can freely interact to form receptors but appear to exhibit considerable preference in the brain as well as ganglia to form mostly receptors of alpha3beta4 and alpha4beta2 subunit composition (150, 471).

a(MESH:Ganglia) increases p(HBP:"alpha-3 beta-2 nAChR") View Subject | View Object

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a(MESH:Ganglia) increases p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

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Evidence b31a1e6cf1
JSON

However, in hippocampal neurons expressing the alpha7, alpha4, and beta2 nAChR subunits, the vast majority of functional nAChRs are pharmacologically identified as being distinctly alpha4beta2 and alpha7 nAChRs (12).

a(MESH:Hippocampus) increases p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

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a(MESH:Hippocampus) increases p(HGNC:CHRNA7) View Subject | View Object

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Evidence fc928116e2
JSON

In the muscle, for example, despite the coexpression of as many as five distinct subunits, only receptors of well-defined stoichiometries are expressed: (alpha1)2beta1deltagamma in noninnervated muscle and (alpha1)2beta1deltaepsilon at mature neuromuscular synapses.

a(MESH:Muscles) association complex(p(HGNC:CHRNA1), p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNG)) View Subject | View Object

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a(MESH:Muscles) association complex(p(HGNC:CHRNA1), p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNE), loc(MESH:"Neuromuscular Junction")) View Subject | View Object

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complex(p(HGNC:CHRNA1), p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNE), loc(MESH:"Neuromuscular Junction")) association a(MESH:Muscles) View Subject | View Object

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complex(p(HGNC:CHRNA1), p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNG)) association a(MESH:Muscles) View Subject | View Object

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Evidence 9503b719d6
JSON

In the immature muscle alpha1, beta1, delta and gamma nAChR subunit transcripts are made and receptors from these subunits are synthesized and transported to the cell surface.

a(MESH:Muscles) increases r(HGNC:CHRNB1) View Subject | View Object

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a(MESH:Muscles) increases r(HGNC:CHRNA1) View Subject | View Object

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a(MESH:Muscles) increases r(HGNC:CHRND) View Subject | View Object

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a(MESH:Muscles) increases r(HGNC:CHRNG) View Subject | View Object

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complex(p(HGNC:CHRNA1), p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNG)) increases complex(p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNG), loc(GO:"cell surface")) View Subject | View Object

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Evidence 7ec53eaf3f
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For example, while the alpha7 nAChR is primarily a homomeric receptor in neurons (127), combinations of alpha7 nAChR subunits with alpha5, beta2, or beta3 nAChR subunits have been reported to form functional heteromeric receptors in some systems (240, 360, 515).

a(MESH:Neurons) association p(HGNC:CHRNA7) View Subject | View Object

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p(HGNC:CHRNA7) association a(MESH:Neurons) View Subject | View Object

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p(HGNC:CHRNA7) association complex(p(HGNC:CHRNA5), p(HGNC:CHRNA7)) View Subject | View Object

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p(HGNC:CHRNA7) association complex(p(HGNC:CHRNA7), p(HGNC:CHRNB2)) View Subject | View Object

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p(HGNC:CHRNA7) association complex(p(HGNC:CHRNA7), p(HGNC:CHRNB3)) View Subject | View Object

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complex(p(HGNC:CHRNA5), p(HGNC:CHRNA7)) association p(HGNC:CHRNA7) View Subject | View Object

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complex(p(HGNC:CHRNA7), p(HGNC:CHRNB2)) association p(HGNC:CHRNA7) View Subject | View Object

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complex(p(HGNC:CHRNA7), p(HGNC:CHRNB3)) association p(HGNC:CHRNA7) View Subject | View Object

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Evidence 1e468f4e76
JSON

Interestingly, astrocytic KYNA production is regulated by neuronal activity (187) and cellular energy metabolism (213). This dependence of extracellular KYNA concentrations on the functional interplay between neurons and astrocytes is in line with the postulated neuromodulatory role of KYNA (418) and adds to the complexity of the neurochemical networks in the brain.

a(MESH:Neurons) regulates a(CHEBI:"kynurenic acid") View Subject | View Object

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bp(GO:"energy homeostasis") regulates a(CHEBI:"kynurenic acid") View Subject | View Object

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Evidence 1c0a60f097
JSON

A similar level of fidelity in nAChR assembly is achieved by cells of the brain. For example, the alpha4, alpha7, and beta2 nAChR interact with each other to form functional receptors in heterologous systems such as oocytes.

a(MESH:Oocytes) association composite(p(HGNC:CHRNA4), p(HGNC:CHRNA7), p(HGNC:CHRNB2)) View Subject | View Object

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composite(p(HGNC:CHRNA4), p(HGNC:CHRNA7), p(HGNC:CHRNB2)) association a(MESH:Oocytes) View Subject | View Object

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Evidence 0a7cae4f0b
JSON

Because of the absence of reuptake or degradation mechanisms, subsequent KYNA removal is accomplished exclusively by probenecid-sensitive brain efflux (330, 473).

a(MESH:Probenecid) decreases a(CHEBI:"kynurenic acid") View Subject | View Object

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Evidence 69a7cfc702
JSON

In addition to nicotine, an nAChR agonist of considerable commercial importance is anatoxin-a (Fig. 3). This toxin is a product of the blue-green algae, Anabaena, and can reach high concentrations during algal blooms common to ponds that serve as the summer water source of livestock. While this toxin exerts much of its effect through targeting muscle nAChRs, it was recognized over two decades ago to also interact with nAChRs expressed by ganglionic receptors (38). Its ability to activate in central nervous system (CNS) neurons nicotinic currents sensitive to alpha-BGT was among the first indicators that functional alpha7 nAChRs could be distinguished from other nAChRs in neurons of the mammalian brain (38).

a(TAXONOMY:1163) increases a(CHEBI:"Anatoxin a") View Subject | View Object

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complex(a(CHEBI:"Anatoxin a"), p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Central Nervous System
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Ganglia
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Muscles
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Evidence b0c355ec39
JSON

More recently, epibatidine, an alkaloid from the skin of the Ecuadorain tree frog Epipedobates tricolor, revealed another example of how a nicotinic agonist can produce toxic effects (111, 130). In addition to being a potent analgesic, when injected into mice at a relatively low dose (0.4 microg/mouse), this compound produced straub tail reaction. The major target of epibatidine is the alpha4beta2 high-affinity nAChR, although other nAChRs are targeted with various affinities (e.g., Ref. 507).

a(TAXONOMY:92736) increases a(CHEBI:epibatidine) View Subject | View Object

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complex(a(CHEBI:epibatidine), p(HBP:"alpha-4 beta-2 nAChR")) increases act(p(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

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complex(a(CHEBI:epibatidine), p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Evidence 268af02b05
JSON

Furthermore, TNF-alpha strongly promotes ligand-mediated upregulation of alpha4beta2 nAChRs through a mechanism that requires p38 mitogen-activated protein kinase (MAPK) signaling (163).

bp(GO:"MAPK cascade") increases act(p(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

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p(HGNC:TNF) increases bp(GO:"MAPK cascade") View Subject | View Object

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Evidence fd94faddc6
JSON

In cell lines, this interaction of trans-activating components is also under the regulation of the Ras-dependent MAPK and pathways related to phosphoinositide-3-kinase (PI3K) and MEK activation whose response to trophic factors such as nerve growth factor (NGF) contributes to regulating transcript initiation.

bp(GO:"MAPK cascade") regulates r(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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bp(GO:"phosphatidylinositol 3-kinase signaling") regulates r(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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act(p(HGNC:NGF)) increases bp(GO:"MAPK cascade") View Subject | View Object

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Evidence de1272ca7f
JSON

It is noteworthy that, via such mechanisms, alpha7 nAChR activation could trigger rebound burst firing in SLM interneurons even in the absence of excitation (256). Burst firing in SLM interneurons suppresses spikes in pyramidal neurons evoked by stimulation of Schaffer collaterals (134), and, thereby allows selective activation of the pyramidal cells via the perforant pathway.

bp(GO:"action potential initiation") decreases a(MESH:"Electric Stimulation", loc(GO:"Schaffer axon collateral")) View Subject | View Object

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Uberon
hippocampus stratum lacunosum moleculare
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bp(GO:"action potential initiation") increases act(a(MESH:"Perforant Pathway")) View Subject | View Object

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Uberon
hippocampus stratum lacunosum moleculare
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act(p(HGNC:CHRNA7)) increases bp(GO:"action potential initiation") View Subject | View Object

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Uberon
hippocampus stratum lacunosum moleculare
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Evidence f501c47187
JSON

In receptors harboring the gamma subunit, agonist-induced receptor activation results in a long-lasting open channel time. The large agonist-induced current in turn leads to local intermittent depolarization and adjustments to protein-protein interactions that favor receptor clustering. As the depolarization increases, transcription of the epsilon subunit is increased dramatically (183).

bp(GO:"depolarization of postsynaptic membrane") increases r(HGNC:CHRNE) View Subject | View Object

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bp(GO:"long-term synaptic potentiation") increases bp(GO:"depolarization of postsynaptic membrane") View Subject | View Object

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act(p(HGNC:CHRNG)) increases bp(GO:"long-term synaptic potentiation") View Subject | View Object

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Evidence ce47082f6f
JSON

If there is intense stimulation of all three nAChRs, the resulting depolarization can trigger activation of voltage- gated Ca2+ channels (VGCC), which in turn would activate the calcineurin pathway and prevent CREB activation.

bp(GO:"depolarization of postsynaptic membrane") increases act(complex(GO:"voltage-gated calcium channel complex")) View Subject | View Object

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act(complex(GO:"voltage-gated calcium channel complex")) increases bp(GO:"calcineurin-mediated signaling") View Subject | View Object

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act(complex(GO:"voltage-gated calcium channel complex")) decreases act(p(FPLX:CREB), ma(tscript)) View Subject | View Object

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Evidence d6962e7096
JSON

Activation of somatodendritic alpha7 nAChRs increases the action potential-dependent release of dopamine, while activation of presynaptic alpha6 and/or alpha4 nAChRs increases action potential-independent dopamine release.

bp(GO:"neuronal action potential") increases sec(a(CHEBI:dopamine)) View Subject | View Object

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act(p(HGNC:CHRNA7)) increases bp(GO:"neuronal action potential") View Subject | View Object

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p(HBP:"alpha-4-containing nAChR") increases sec(a(CHEBI:dopamine)) View Subject | View Object

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p(HBP:"alpha-6-containing nAChR") increases sec(a(CHEBI:dopamine)) View Subject | View Object

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Evidence beaba9d281
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Also central to restricting (or at least limiting) the expression of these transcripts to predominantly neuronal-like cell lines (Neuro2A and NGF-treated PC12) are interactions among other factors including SCIP/Tst- 1/Oct-6 and transactivation by Sox10 (66, 268, 317, 513).

act(p(HGNC:SOX10)) increases r(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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Evidence a4dbe4cdd2
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AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation.

bp(GO:"synaptic transmission, cholinergic") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:Dementia) View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Plaque, Amyloid") View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Neurofibrillary Tangles") View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Neurogenic Inflammation") View Subject | View Object

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path(MESH:"Neurofibrillary Tangles") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Neurogenic Inflammation") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Plaque, Amyloid") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:Dementia) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Evidence 13e325ca64
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In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).

bp(GO:cognition) positiveCorrelation p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

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bp(GO:cognition) positiveCorrelation p(HGNC:CHRNA7) View Subject | View Object

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p(HGNC:CHRNA7) positiveCorrelation bp(GO:cognition) View Subject | View Object

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p(HGNC:CHRNA7) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HBP:"alpha-4 beta-2 nAChR") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HBP:"alpha-4 beta-2 nAChR") positiveCorrelation bp(GO:cognition) View Subject | View Object

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g(HGNC:CHRNA7) association path(MESH:"Sensory Gating") View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA7) View Subject | View Object

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path(MESH:"Sensory Gating") association g(HGNC:CHRNA7) View Subject | View Object

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path(MESH:"Sensory Gating") association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Schizophrenia) association path(MESH:"Sensory Gating") View Subject | View Object

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Evidence 3538a56a76
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When cRNAs encoding specific nAChR subunits are introduced into Xenopus oocytes, simple (alpha3beta4) as well as more complex (muscle alpha1beta1deltagamma) heteromeric receptors are assembled and expressed on the cell surface (341). In Xenopus oocytes, these heteromeric nAChRs are assembled and expressed with almost equivalent efficiencies as the homomeric 5HT3A receptor (341).

bp(HBP:"nAChR assembly") increases p(HBP:"alpha-3 beta-4 nAChR", loc(GO:"cell surface")) View Subject | View Object

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bp(HBP:"nAChR assembly") increases complex(p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNG), loc(GO:"cell surface")) View Subject | View Object

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r(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") increases bp(HBP:"nAChR assembly") View Subject | View Object

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Evidence 5eaa0ec0e5
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In the basal ganglia, for instance, dopaminergic transmission is ultimately regulated by the activity of specific nAChR subtypes in different neurons and neuronal compartments (Fig. 5). Thus evidence exists that in the VTA,alpha6- andalpha4-containing nAChRs are mainly located on dopaminergic nerve terminals, whereas alpha7 nAChRs are primarily expressed on the soma of dopaminergic neurons (Fig. 5).

act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) regulates bp(GO:"synaptic transmission, dopaminergic") View Subject | View Object

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Basal Ganglia
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Evidence 49f9348f08
JSON

Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432).

act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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path(MESH:Schizophrenia) negativeCorrelation act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Evidence 785c57fb87
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However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374).

p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") negativeCorrelation path(MESH:Aging) View Subject | View Object

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p(HGNC:CHRNA4) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA4) View Subject | View Object

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path(MESH:Aging) negativeCorrelation p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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Evidence 50d7afa39b
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It is noteworthy that nAChR expression by astrocytes in brains afflicted with AD is increased (463, 518), and astrocytes in general have been reported to be more plentiful in the hippocampus of some rat strains with age (35, 284).

p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Astrocytes
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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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Astrocytes
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Evidence f0961c47ef
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It has long been recognized that nAChR activation in mammalian sympathetic neurons induces the opening of a nonselective cation channel that leads to Na+ influx, membrane depolarization, and consequently activation of voltage-gated Ca2+ channels (92, 119).

act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) increases bp(GO:"cation transport") View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) increases a(MESH:Sodium, loc(GO:intracellular)) View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) increases bp(GO:"membrane depolarization") View Subject | View Object

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act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) increases bp(GO:"positive regulation of voltage-gated calcium channel activity") View Subject | View Object

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Evidence e3d5d6aa11
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Long before the identification of the high Ca2+ permeability of alpha7 nAChR channels, different studies reported significant Ca2+ influx through nAChRs in muscle, parasympathetic neurons, pheochromocytoma cells, and human neuroblastoma cells (115, 321, 347, 407, 411, 459, 468).

act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) increases a(CHEBI:"calcium(2+)", loc(GO:intracellular)) View Subject | View Object

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Muscles
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PC12 Cells
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Parasympathetic Nervous System
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act(p(HGNC:CHRNA7)) increases a(CHEBI:"calcium(2+)", loc(GO:intracellular)) View Subject | View Object

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Evidence 82413f2934
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There is current evidence that nAChRs present in skin cells modulate the responses triggered by inflammatory stimuli applied to the skin (354). Smoking is a welldefined risk factor in delayed wound healing and possibly the development of premature facial wrinkling (226).

p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") regulates bp(GO:"inflammatory response") View Subject | View Object

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Skin
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path(MESH:"Tobacco Use Disorder") decreases path(MESH:"Wound Healing") View Subject | View Object

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Skin
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path(MESH:"Tobacco Use Disorder") increases path(MESH:"Skin Aging") View Subject | View Object

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Skin
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Evidence aab07d19e4
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In CA1 and CA3 pyramidal neurons of the developed hippocampus, alpha7 nAChRs are expressed primarily on axon terminals whereby their activation modulates the efficacy of glutamate synaptic transmission.

act(p(HGNC:CHRNA7, loc(GO:"axon terminus"))) regulates bp(GO:"synaptic transmission, glycinergic") View Subject | View Object

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CA1 Region, Hippocampal
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CA3 Region, Hippocampal
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Pyramidal Cells
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Evidence 7a3ce43539
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Several possibilities exist for the identity of the nAChR important to tolerance development. The strong positive correlation between alpha-BGT site number and sensitivity to nicotine-induced seizures among multiple mouse strains led to the suggestion that alpha7 nAChRs are critical to limit oral nicotine self-administration in mice (105, 301).

p(HGNC:CHRNA7) regulates a(CHEBI:nicotine) View Subject | View Object

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Evidence 4cae1ca115
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While development of tolerance does not seem to be regulated by alpha7 nAChRs, a recent study of alpha7 nAChR-null mice indicates that these receptors control the severity of the nicotine withdrawal syndrome (402).

p(HGNC:CHRNA7) regulates path(MESH:"Substance Withdrawal Syndrome") View Subject | View Object

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Evidence f92ac94bb8
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As will be returned to below, it is also the first nAChR subtype to exhibit measurable decline in expression in the aged mammalian brain and especially in neurodegenerative disorders such as AD (236, 374).

p(HBP:"alpha-4 beta-2 nAChR") negativeCorrelation path(MESH:Aging) View Subject | View Object

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p(HBP:"alpha-4 beta-2 nAChR") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

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path(MESH:Aging) negativeCorrelation p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

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Evidence b03050563f
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Genetic deletion of the alpha4 or the alpha2 nAChR subunit abolishes essentially all high-affinity nicotine binding to brain tissue and upregulation in response to chronic exposure to nicotine (151, 311).

p(HBP:"alpha-4 beta-2 nAChR") increases complex(a(CHEBI:nicotine), p(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

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Evidence a4092ce39c
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A concurrent activation of preterminal alpha4beta2 nAChRs would hyperpolarize the neuron via GABAergic inhibition and prevent activation of the VGCC.

act(p(HBP:"alpha-4 beta-2 nAChR")) decreases bp(GO:"synaptic transmission, GABAergic") View Subject | View Object

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act(p(HBP:"alpha-4 beta-2 nAChR")) decreases act(complex(GO:"voltage-gated calcium channel complex")) View Subject | View Object

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Evidence 7563843936
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Activation of alpha4beta2 nAChRs on GABAergic interneurons in the VTA relieves the inhibitory control they exert on dopaminergic neurons (295, 380).

act(p(HBP:"alpha-4 beta-2 nAChR", loc(MESH:"GABAergic Neurons"))) increases act(a(MESH:"Dopaminergic Neurons")) View Subject | View Object

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Ventral Tegmental Area
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Evidence ac13c7f6cc
JSON

Several E26 transformation-specific sequence (ETS) factor binding sites were identified that upon deletion led to substantially diminished expression of both alpha3 and beta4, and to direct transgene expression of the reporter gene, LacZ, to major sites of gene cluster expression in multiple brain regions, ganglia, and peripheral systems.

p(HGNCGENEFAMILY:"ETS transcription factor family") association r(HGNC:CHRNA3) View Subject | View Object

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p(HGNCGENEFAMILY:"ETS transcription factor family") association r(HGNC:CHRNB4) View Subject | View Object

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r(HGNC:CHRNA3) association p(HGNCGENEFAMILY:"ETS transcription factor family") View Subject | View Object

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r(HGNC:CHRNB4) association p(HGNCGENEFAMILY:"ETS transcription factor family") View Subject | View Object

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Evidence 764eddcfdc
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Such toxins are not limited to the muscle receptor as seen in the Taiwanese krate snake. This snake produces “neuronal bungarotoxin” (also referred to as 3.1 toxin or kappa-bungarotoxin; Ref. 286), which preferentially binds to and inactivates neuronal nAChRs that contain the alpha3 and beta4 subunits. In this case, the specificity of the toxin appears to in part be controlled by the subtype of beta nAChR subunit; beta2-containing nAChRs are less sensitive than beta4-containing nAChRs to inhibition by neuronal BGT.

complex(a(HBP:"kappa-Bungarotoxin"), p(HBP:"alpha-3 beta-4 nAChR")) decreases act(p(HBP:"alpha-3 beta-4 nAChR")) View Subject | View Object

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complex(a(HBP:"kappa-Bungarotoxin"), p(HGNC:CHRNB4)) decreases act(p(HGNC:CHRNB4)) View Subject | View Object

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Evidence 30615522aa
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Additional examples of snake toxins include alpha-cobratoxin (Fig. 3), which binds to the agonist binding site of the receptor and blocks receptor activation.

complex(a(MESH:"alpha-cobratoxin"), p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Evidence 143a2752b5
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Finally, the alkaloid methyllycaconitine (MLA) emerged as a potent and specific competitive antagonist that inhibits muscle, alpha7-, alpha6-, and alpha3-containing nAChRs (30, 326, 445). The alkaloid is derived from the larkspur (genus Delphinium), which is of great economic interest since estimates of its cost to ranchers in poisoned livestock exceeds many millions of dollars annually. Similar to most nAChR poisons, MLA binds to the receptor agonistbinding site (Fig. 3) in a manner similar to that of alpha-BGT to block agonist binding and receptor activation.

complex(a(MESH:methyllycaconitine), p(HGNC:CHRNA3)) decreases act(p(HGNC:CHRNA3, loc(MESH:Muscles))) View Subject | View Object

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complex(a(MESH:methyllycaconitine), p(HGNC:CHRNA6)) decreases act(p(HGNC:CHRNA6, loc(MESH:Muscles))) View Subject | View Object

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complex(a(MESH:methyllycaconitine), p(HGNC:CHRNA7)) decreases act(p(HGNC:CHRNA7, loc(MESH:Muscles))) View Subject | View Object

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Evidence aa8036f725
JSON

The epsilon subunit protein outcompetes the gamma subunit for assembly into the receptor. The receptors assembled with the epsilon subunit are more stable to degradation, aggregate at the neuromuscular junction to greater density and exhibit a more rapid response to agonist (96, 275, 324).

complex(p(HGNC:CHRNA1), p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNE)) decreases deg(complex(p(HGNC:CHRNA1), p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNE))) View Subject | View Object

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r(HGNC:CHRNE) decreases complex(p(HGNC:CHRNA1), p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNG)) View Subject | View Object

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r(HGNC:CHRNE) increases complex(p(HGNC:CHRNA1), p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNE)) View Subject | View Object

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Evidence a88163e27d
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Green and colleagues (191, 365, 485) report that nAChR assembly proceeds in the endoplasmic reticulum where specific subunits are added sequentially to the receptor complex according to the conformations the complex assumes. In this model, nAChR subunits are synthesized, and initial polypeptide folding favors the rapid recognition and interaction between alpha-beta-gamma subunits to produce trimers that in turn form a structure favorable to the addition of the delta subunit and finally the second alpha subunit.

complex(p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNG), loc(GO:"endoplasmic reticulum")) increases complex(p(HGNC:CHRNA1), p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNG)) View Subject | View Object

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complex(p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRNG), loc(GO:"endoplasmic reticulum")) increases complex(p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNG)) View Subject | View Object

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composite(p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRNG), loc(GO:"endoplasmic reticulum")) increases complex(p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRNG)) View Subject | View Object

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Evidence 8583064e1f
JSON

Subsequent studies have revealed that the DNA binding Sp-1 transcriptional factor interacts in response to NGF with the c-Jun coactivator (317) to increase beta4 transcription.

act(complex(p(HGNC:JUN), p(HGNC:SP1)), ma(tscript)) increases r(HGNC:CHRNB4) View Subject | View Object

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act(p(HGNC:NGF)) increases complex(p(HGNC:JUN), p(HGNC:SP1)) View Subject | View Object

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Evidence db2119c8e5
JSON

Upon transfection of the cDNA encoding alpha7 nAChR subunits, HEK293 cells reportedly express the corresponding transcripts and even make considerable protein. Yet, the number of functional receptors expressed on the cell surface was low and could vary by three orders of magnitude.

composite(a(MESH:"HEK293 Cells"), g(HGNC:CHRNA7)) decreases act(p(HGNC:CHRNA7)) View Subject | View Object

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Experimental Factor Ontology (EFO)
HEK293
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Evidence 205c6ee355
JSON

Only two of these cell lines expressed alpha7 nAChRs: GH4C1 cells expressed substantially greater numbers of surface receptors than did SH-EP1 cells, which exhibited poor assembly efficiency.

g(HGNC:CHRNA7) increases p(HGNC:CHRNA7) View Subject | View Object

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GH4-C1 cell
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composite(g(HGNC:CHRNA4), g(HGNC:CHRNB2)) increases complex(p(HGNC:CHRNA4), p(HGNC:CHRNB2)) View Subject | View Object

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GH4-C1 cell
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Evidence e7b095ac32
JSON

In another model, a somewhat different route to assembly is proposed (59, 435, 493). In this scenario, dimers between alpha-gamma and alpha-delta subunits are formed before these paired subunits subsequently interact with the beta subunit to assemble the mature pentamer.

composite(complex(p(HGNC:CHRNA1), p(HGNC:CHRND)), complex(p(HGNC:CHRNA1), p(HGNC:CHRNG)), p(HGNC:CHRNB1)) increases complex(p(HGNC:CHRNA1), p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNG)) View Subject | View Object

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Evidence a7748456b2
JSON

For example, in the original PC12 line (194), NGF is a potent inducer of beta4 transcription (217), but in PC12 lines that are defective in the expression of functional alpha7 nAChRs, NGF decreases beta4 nAChR subunit transcription (60, 397).

composite(p(HGNC:CHRNA7), p(HGNC:NGF)) increases r(HGNC:CHRNB4) View Subject | View Object

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PC12 Cells
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Evidence f3f4e616c8
JSON

As was noted above, in different laboratories, these cells were reported to regulate nAChR mRNA expression differently in response to nerve growth factor, and to exhibit dramatically different expression of alpha7 nAChRs.

p(HGNC:NGF) regulates r(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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Evidence c8be91f866
JSON

In the basal ganglia, including the ventral tegmental area (VTA) and substantia nigra, the alpha6 and possibly the beta3 nAChR subunits are included in alpha4beta2 nAChR complexes to generate highaffinity receptors. At present, this is the only brain area identified where alpha6 and beta3 are coexpressed with alpha4 and beta2 nAChR subunits. This finding is highly relevant for Parkinson’s disease (385, 386).

p(HBP:"alpha-6 alpha-4 beta-2 beta-3 nAChR", loc(MESH:"Basal Ganglia")) association path(MESH:"Parkinson Disease") View Subject | View Object

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path(MESH:"Parkinson Disease") association p(HBP:"alpha-6 alpha-4 beta-2 beta-3 nAChR", loc(MESH:"Basal Ganglia")) View Subject | View Object

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Evidence f672049159
JSON

Receptors composed of alpha7 subunits are known to desensitize rapidly and to have a high Ca2+:Na+ permeability ratio that exceeds that of the glutamate NMDA receptor, and the 3-4:1 ratio of most other nAChRs (8, 68, 78, 387). As a result, quite distinctly from other nAChRs and even other ligand-activated ion channels, the opening of alpha7 nAChR channels can impact on several Ca2+-dependent mechanisms, including activation of second messenger pathways (328, 456).

p(HBP:"alpha-7-containing nAChR") increases bp(GO:"calcium ion transport into cytosol") View Subject | View Object

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Evidence e7c9f38238
JSON

At the neuromuscular junction, nicotinic function is enhanced by inhibition of acetylcholinesterase (AChE), the enzyme that metabolizes the endogenous neurotransmitter ACh.

p(HGNC:ACHE) decreases act(a(CHEBI:nicotine)) View Subject | View Object

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Neuromuscular Junction
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Evidence e791cd239c
JSON

Studies of recombinant chimeric subunits containing sequences of the NH2-terminal domains of the alpha7 and the alpha3 (M1-S232) nAChR subunits indicated that a 23- amino acid region (glycine-23 to asparagine-46) contained residues required for correct association of the alpha7 subunit into a homopentameric receptor.

p(HGNC:CHRNA7, frag("23_46")) increases complex(p(HGNC:CHRNA7), p(HGNC:CHRNA7)) View Subject | View Object

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Evidence 788123dec4
JSON

In the brain, however, Cox2 is constitutively expressed by neurons (212, 512), participates in modulating synaptic plasticity (53, 464), and conditionally can either inhibit or promote cell death (74, 85, 237, 322, 451).

p(HGNC:PTGS2, loc(MESH:Neurons)) regulates path(MESH:"Neuronal Plasticity") View Subject | View Object

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Brain
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p(HGNC:PTGS2, loc(MESH:Neurons)) regulates bp(GO:"cell death") View Subject | View Object

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Brain
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Evidence 35a58e6368
JSON

Mouse strains, like humans, also exhibit a striking age-related decline in nAChR expression. For instance, in the hippocampus of aged CBA and B6 mice, expression of alpha4 and alpha7 nAChR subunits decreases with age (166).

p(MGI:Chrna4) negativeCorrelation path(MESH:Aging) View Subject | View Object

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Hippocampus
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p(MGI:Chrna7) negativeCorrelation path(MESH:Aging) View Subject | View Object

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Hippocampus
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path(MESH:Aging) negativeCorrelation p(MGI:Chrna4) View Subject | View Object

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Hippocampus
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path(MESH:Aging) negativeCorrelation p(MGI:Chrna7) View Subject | View Object

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Hippocampus
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Evidence 559e17b666
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The importance of retaining the high-affinity nicotine binding sites to brain integrity has been demonstrated in studies of mice with a null mutation in the gene that encodes the beta2 nAChR subunit, a structural subunit of the high-affinity nicotine binding site (150, 184, 215, 311); these mice experience early onset neurodegeneration (528).

p(MGI:Chrnb2) negativeCorrelation path(HBP:Neurodegeneration) View Subject | View Object

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path(HBP:Neurodegeneration) negativeCorrelation p(MGI:Chrnb2) View Subject | View Object

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Evidence 5589ed1296
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It has long been known that smokers tend to be leaner, and yet approximately four times more likely to become insulin resistant and develop type I diabetes (497), a condition that is more commonly observed in obese patients.

path(MESH:"Insulin Resistance") association path(MESH:"Tobacco Use Disorder") View Subject | View Object

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path(MESH:"Insulin Resistance") increases path(MESH:"Diabetes Mellitus, Type 1") View Subject | View Object

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path(MESH:"Tobacco Use Disorder") association path(MESH:"Insulin Resistance") View Subject | View Object

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Evidence d80426bead
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However, epidemiological studies have reported that heavy smokers are less likely to experience PD (see reviews in Refs. 384, 385).

path(MESH:"Parkinson Disease") negativeCorrelation path(MESH:"Tobacco Use Disorder") View Subject | View Object

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path(MESH:"Tobacco Use Disorder") negativeCorrelation path(MESH:"Parkinson Disease") View Subject | View Object

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Evidence b41b17358f
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In fact, the relationship between tobacco abuse (including smokeless) and difficulty in healing, increased susceptibility to infection (especially oral), enhanced expression of indicators of skin aging, and increased cancer risk are all well-documented (383, 452).

path(MESH:"Skin Aging") association path(MESH:"Tobacco Use Disorder") View Subject | View Object

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path(MESH:"Tobacco Use Disorder") decreases path(MESH:"Wound Healing") View Subject | View Object

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path(MESH:"Tobacco Use Disorder") association path(MESH:Infection) View Subject | View Object

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path(MESH:"Tobacco Use Disorder") association path(MESH:"Skin Aging") View Subject | View Object

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path(MESH:"Tobacco Use Disorder") association path(MESH:Neoplasms) View Subject | View Object

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path(MESH:Infection) association path(MESH:"Tobacco Use Disorder") View Subject | View Object

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path(MESH:Neoplasms) association path(MESH:"Tobacco Use Disorder") View Subject | View Object

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About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.