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  3. PubMed:19721446

PubMed: 19721446

Title
Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system.
Journal
Nature reviews. Drug discovery
Volume
8
Issue
None
Pages
733-50
Date
2009-09-01
Authors
Changeux JP | Corringer PJ | Guedin D | Lestage P | Taly A

Evidence 6729572f09
JSON

As with nicotine, the weak alpha7 nAChR agonist GTS-21 is neuroprotective, specifically protecting against Abeta1–42-elicited neurotoxicity154. This effect is probably due to small, protracted increases in receptor-mediated Ca2+ influx. importantly, high concentrations of GTS-21 reduced cell survival, underlining the possible risk of over-stimulation152

a(CHEBI:"amyloid-beta polypeptide 42") increases path(HBP:neurotoxicity) View Subject | View Object

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a(MESH:"3-(2,4-dimethoxybenzylidene)anabaseine") increases bp(MESH:Neuroprotection) View Subject | View Object

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a(MESH:"3-(2,4-dimethoxybenzylidene)anabaseine") decreases act(a(CHEBI:"amyloid-beta polypeptide 42")) View Subject | View Object

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a(MESH:"3-(2,4-dimethoxybenzylidene)anabaseine") decreases bp(MESH:"Cell Survival") View Subject | View Object

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Evidence de18372b18
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Regardless of the exact effect of Abeta1–42 on receptor activity, it does seem to block the activation by nicotine and, consistent with the cytoprotective nature of this interaction, amyloid deposition limits neuroprotection151. This phenomenon may explain at least part of the neurotoxicity that is associated with Abeta1–42 (ReF. 156).

a(CHEBI:"amyloid-beta polypeptide 42") increases path(HBP:neurotoxicity) View Subject | View Object

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

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a(CHEBI:"amyloid-beta polypeptide 42") decreases bp(MESH:Neuroprotection) View Subject | View Object

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

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Evidence f7ef219b32
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Most neuronal nAChRs, including alpha4beta2 and alpha7, are potentiated by Ca2+ at millimolar concentrations50.

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

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

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Evidence b666b91ad4
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in parallel, a voltage-dependent inhibitory Zn2+-binding site has been identified within the beta2 subunit of the alpha4beta2 nAChR48.

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

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Evidence 69ccd66d48
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early studies indicated that acute nicotine administration improved performance of patients with Alzheimer’s disease in cognitive tasks, whereas acute administration of the non-competitive (channel blocker) antagonist mecamylamine resulted in dose-dependent impairment of performance in a battery of cognitive tasks137–141

a(CHEBI:Mecamylamine) decreases bp(GO:cognition) View Subject | View Object

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Alzheimer Disease
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a(CHEBI:nicotine) increases bp(GO:cognition) View Subject | View Object

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Alzheimer Disease
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Evidence cb9a0123d9
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The acute effect of ACh consists of the fast opening (microsecond to millisecond range) of a cationic channel that is permeable to Na+, K+ and sometimes Ca2+ ions.

a(CHEBI:acetylcholine) association bp(GO:"regulation of cation channel activity") View Subject | View Object

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bp(GO:"regulation of cation channel activity") association a(CHEBI:acetylcholine) View Subject | View Object

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Evidence de377ac6ce
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Cholesterol is known to be crucial to nAChR function, and it interacts within the transmembrane domain between TM1, TM3 and TM4 (ReF. 57).

a(CHEBI:cholesterol) 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:cholesterol) View Subject | View Object

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Evidence 2d8eb1ca42
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Choline, like nicotine, can protect neural cells from cytotoxicity that is induced by growth factor deprivation152 or exposure to the glutamate analogue AMPA (alpha-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid)153.

a(CHEBI:choline) increases bp(MESH:Neuroprotection) View Subject | View Object

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a(CHEBI:choline) decreases act(a(MESH:"alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid")) View Subject | View Object

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a(MESH:"alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid") increases path(HBP:neurotoxicity) View Subject | View Object

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Evidence c22f9324dd
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However, the atypical antipsychotic drug clozapine normalizes auditory gating in DBA/2 mice — an effect which involves an alpha7 nAChR mechanism181.

a(CHEBI:clozapine) increases bp(MESH:"Sensory Gating") View Subject | View Object

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

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

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Evidence 20205c7079
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Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake.

a(CHEBI:fluoxetine) decreases a(CHEBI:monoamine) View Subject | View Object

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Neurons
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a(CHEBI:fluoxetine) decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Neurons
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a(CHEBI:nefazodone) decreases a(CHEBI:monoamine) View Subject | View Object

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Neurons
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a(CHEBI:nefazodone) decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Neurons
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a(CHEBI:nisoxetine) decreases a(CHEBI:monoamine) View Subject | View Object

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Neurons
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a(CHEBI:nisoxetine) decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Neurons
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a(CHEBI:nomifensine) decreases a(CHEBI:monoamine) View Subject | View Object

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Neurons
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a(CHEBI:nomifensine) decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Neurons
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a(CHEBI:paroxetine) decreases a(CHEBI:monoamine) View Subject | View Object

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Neurons
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a(CHEBI:paroxetine) decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Neurons
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a(CHEBI:sertraline) decreases a(CHEBI:monoamine) View Subject | View Object

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Neurons
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a(CHEBI:sertraline) decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Neurons
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a(CHEBI:vanoxerine) decreases a(CHEBI:monoamine) View Subject | View Object

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Neurons
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a(CHEBI:vanoxerine) decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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Neurons
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Evidence 4eac95639d
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Two compounds that are currently in clinical use might have direct effects on the alpha7 nAChR. The anticholinesterase inhibitor galantamine has modulatory effects on alpha7 nAChR and was reportedly beneficial for patients with schizophrenia in a case study184

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

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a(CHEBI:galanthamine) decreases path(MESH:Schizophrenia) View Subject | View Object

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Evidence e509c42f74
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Chronic exposure to nicotine causes a striking increase, typically by twofold, in the total number of high-affinity receptors — a process termed upregulation8.

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

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Evidence 62c373ffa3
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The alpha7 nAChR has previously been implicated in the in vitro neuroprotective effects of nicotine, using PC12 cells151.

a(CHEBI:nicotine) association bp(MESH:Neuroprotection) View Subject | View Object

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Experimental Factor Ontology (EFO)
PC12
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bp(MESH:Neuroprotection) association p(HGNC:CHRNA7) View Subject | View Object

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PC12
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bp(MESH:Neuroprotection) association a(CHEBI:nicotine) View Subject | View Object

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PC12
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p(HGNC:CHRNA7) association bp(MESH:Neuroprotection) View Subject | View Object

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PC12
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Evidence 0b56186968
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Amyloid plaques form in the entorhinal cortex of patients with Alzheimer’s disease and this region, which connects the neocortex and the hippocampus, plays a crucial part in memory. it has been suggested that plaques in this region represent the lytic remnants of degenerated, Abeta1–42-burdened pyramidal neurons, and that amyloid internalization depends on alpha7 nAChR mediated Ca2+ entry162. Of interest, chronic nicotine treatment has been shown to reduce the plaque burden in animal models of Alzheimer’s disease123.

a(CHEBI:nicotine) decreases path(MESH:"Plaque, Amyloid") View Subject | View Object

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Alzheimer Disease
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a(MESH:"Entorhinal Cortex") association bp(GO:memory) View Subject | View Object

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Entorhinal Cortex
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bp(GO:memory) association a(MESH:"Entorhinal Cortex") View Subject | View Object

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Entorhinal Cortex
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path(MESH:"Alzheimer Disease") increases path(MESH:"Plaque, Amyloid") View Subject | View Object

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Entorhinal Cortex
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Evidence 31f7a269af
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Patients with schizophrenia174 and DBA/2 mouse models180,181 respond to nicotine administration with improved sensory gating, presumably through alpha7 nAChR activation182,183.

a(CHEBI:nicotine) increases bp(MESH:"Sensory Gating") View Subject | View Object

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Schizophrenia
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Evidence 1bd3fee9f6
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Moreover, nAChRs containing β4, α2 and α5 in the habenulo-interpeduncular systems are necessary for nicotine withdrawal in mice107

act(a(CHEBI:nicotine)) association p(HGNC:CHRNB4) View Subject | View Object

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Corpus Striatum
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act(a(CHEBI:nicotine)) association p(HGNC:CHRNA2) View Subject | View Object

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Corpus Striatum
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act(a(CHEBI:nicotine)) association p(HGNC:CHRNA5) View Subject | View Object

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Corpus Striatum
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p(HGNC:CHRNB4) association act(a(CHEBI:nicotine)) View Subject | View Object

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Corpus Striatum
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p(HGNC:CHRNA5) association act(a(CHEBI:nicotine)) View Subject | View Object

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Corpus Striatum
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p(HGNC:CHRNA2) association act(a(CHEBI:nicotine)) View Subject | View Object

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Corpus Striatum
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Evidence e465c31565
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Also, α7- and non-α7-containing nicotinic receptors directly or indirectly (through GABAergic interneurons) modulate serotonin release in spinal cord slices230. However, the identity of the receptors that are responsible for the spinal control of nociception is currently unknown. in this process, the nicotine-induced antinociception seems to be mediated primarily by activation of calcium– calmodulin-dependent protein kinase 2, but this is not the case for supraspinal nociception control229.

act(a(CHEBI:nicotine)) decreases path(MESH:Nociception) View Subject | View Object

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a(MESH:"Receptors, Nicotinic") regulates sec(a(CHEBI:serotonin)) View Subject | View Object

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

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Evidence 13d37ed47d
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Nicotine facilitates dopamine release by acting at both somatodendritic and presynaptic nAChRs on mesolimbic246,247 and nigrostriatal247 neurons.

a(CHEBI:nicotine) regulates sec(a(CHEBI:dopamine)) View Subject | View Object

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Evidence 7219f445a9
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Similarly, topisetron, a 5HT3 antagonist marketed outside the united States as an anti-nausea drug, also has efficacy as an alpha7 nAChR agonist and increases the inhibition of P50 auditory gating in schizophrenia185.

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

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Schizophrenia
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a(CHEBI:tropisetron) decreases bp(MESH:"Sensory Gating") View Subject | View Object

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Schizophrenia
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Evidence e1d3870923
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varenicline (Chantix/Champix; Pfizer), the most recently approved drug for smoking cessation which is now on the market, is a partial agonist at alpha4beta2 nAChRs, and a full agonist at alpha7 nAChRs (ReF. 200).

a(CHEBI:varenicline) increases path(MESH:"Smoking Cessation") View Subject | View Object

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

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

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Evidence edfd4c7d9c
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Two partial agonists of alpha7 nAChRs, GTS-21 (also a strong alpha4beta2 antagonist) and MeM-3454 (also a strong 5-hydroxytryptamine type 3 receptor (5HT3) antagonist)149 (TABLe 1), further showed a procognitive action and, in preclinical studies, MeM-3454 enhanced episodic, spatial and working memory.

a(DRUGBANK:Facinicline) increases bp(GO:cognition) View Subject | View Object

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a(DRUGBANK:Facinicline) increases bp(GO:memory) View Subject | View Object

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a(MESH:"3-(2,4-dimethoxybenzylidene)anabaseine") increases bp(GO:cognition) View Subject | View Object

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Evidence 16ee88f6b3
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Similarly, MeM-3454 improved the ‘quality of episodic secondary memory’ score, which is a measure of episodic memory. As for episodic memory, working memory is impaired in Alzheimer’s disease. MeM-3454 significantly improved the quality of working memory score in patients with Alzheimer’s disease in Phase i trials. in a Phase ii trial, the quality of working memory scores were also improved by MeM-3454, as was the ADAS–cog (Alzheimer’s disease assessment scale–cognitive subscale) score.

a(DRUGBANK:Facinicline) increases path(MESH:"Memory, Episodic") View Subject | View Object

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path(MESH:"Alzheimer Disease") decreases path(MESH:"Memory, Episodic") View Subject | View Object

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Evidence bd04544a7e
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The binding site on alpha7 nAChRs63,64 for the positive allosteric modulators PNu-120596 and lY-2087101, has been tentatively identified within the transmembrane domain. it comprises five amino acids within TM1, TM2 and TM4 which, when mutated, substantially reduce the potentiation of alpah7 nAChRs by allosteric modulators

act(a(MESH:"1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea")) association p(HGNC:CHRNA7, frag("231_255")) View Subject | View Object

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act(a(MESH:"1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea")) association p(HGNC:CHRNA7, frag("262_280")) View Subject | View Object

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act(a(MESH:"1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea")) association p(HGNC:CHRNA7, frag("470_490")) View Subject | View Object

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act(a(PUBCHEM:11964458)) association p(HGNC:CHRNA7, frag("231_255")) View Subject | View Object

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act(a(PUBCHEM:11964458)) association p(HGNC:CHRNA7, frag("262_280")) View Subject | View Object

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act(a(PUBCHEM:11964458)) association p(HGNC:CHRNA7, frag("470_490")) View Subject | View Object

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p(HGNC:CHRNA7, frag("231_255")) association act(a(MESH:"1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea")) View Subject | View Object

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p(HGNC:CHRNA7, frag("231_255")) association act(a(PUBCHEM:11964458)) View Subject | View Object

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p(HGNC:CHRNA7, frag("262_280")) association act(a(MESH:"1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea")) View Subject | View Object

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p(HGNC:CHRNA7, frag("262_280")) association act(a(PUBCHEM:11964458)) View Subject | View Object

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p(HGNC:CHRNA7, frag("470_490")) association act(a(MESH:"1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea")) View Subject | View Object

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p(HGNC:CHRNA7, frag("470_490")) association act(a(PUBCHEM:11964458)) View Subject | View Object

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Evidence 2cebc2c340
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in a small Phase i clinical trial, GTS-21 improved episodic secondary memory tasks, including word recall, and picture and word recognition1

a(MESH:"3-(2,4-dimethoxybenzylidene)anabaseine") increases path(MESH:"Memory, Episodic") View Subject | View Object

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Evidence a0fa33f526
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GTS-21, one of a series of compounds derived from anabaseine, an alkaloid found in marine worms, is a partial agonist of alpha7 nAChRs that improves memory-related behaviours in various paradigms and normalizes auditory gating186. it is the leading clinical candidate in the field of alpha7 nAChRs.

a(MESH:"3-(2,4-dimethoxybenzylidene)anabaseine") increases bp(MESH:"Sensory Gating") View Subject | View Object

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a(MESH:"3-(2,4-dimethoxybenzylidene)anabaseine") increases act(p(HGNC:CHRNA7)) View Subject | View Object

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Evidence a5e340144c
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initially evaluated in normal subjects, GTS-21 was found to significantly improve attention and memory. in a second Phase i trial187, GTS-21 normalized P50 auditory gating in patients with schizophrenia.

a(MESH:"3-(2,4-dimethoxybenzylidene)anabaseine") increases bp(MESH:"Sensory Gating") View Subject | View Object

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a(MESH:"3-(2,4-dimethoxybenzylidene)anabaseine") increases bp(GO:memory) View Subject | View Object

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a(MESH:"3-(2,4-dimethoxybenzylidene)anabaseine") increases path(MESH:Attention) View Subject | View Object

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Evidence dc76aff12d
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Both initiatives were successful: new compounds — A-366833 and ABT-894 — with improved α4β2 selectivity and a broad spectrum of analgesic efficacy without adverse effects were identified236. ABT-894 was chosen to go into Phase ii clinical trials but the results were disappointing, and the development of this compound for neuropathic pain has been discontinued. The compound remains in clinical trials for ADHD.

a(MESH:"3-(5,6-dichloropyridin-3-yl)-3,6-diazabicyclo(3.2.0)heptane") increases act(p(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

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Evidence 2bb2021de5
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ABT-418, discussed above, has also been found to be active in a limited human trial in attention deficit hyperactivity disorder (ADHD)171. A second compound, ABT-089, which is a partial agonist at alpha4beta2 nAChRs, was also efficacious in ADHD172

a(MESH:"3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole") association path(MESH:"Attention Deficit Disorder with Hyperactivity") View Subject | View Object

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a(MESH:pozanicline) association path(MESH:"Attention Deficit Disorder with Hyperactivity") View Subject | View Object

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path(MESH:"Attention Deficit Disorder with Hyperactivity") association a(MESH:"3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole") View Subject | View Object

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path(MESH:"Attention Deficit Disorder with Hyperactivity") association a(MESH:pozanicline) View Subject | View Object

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Evidence c9d1889616
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The first nicotinic receptor ligand to undergo Phase ii clinical trials for analgesic activity was the potent Abbott compound ABT-594, a nAChR agonist that preferentially targets α4β2 (ReFS 231–235). The compound allowed for the clinical proof of concept, but could not be developed further because of adverse effects such as emesis and nausea236. As these adverse effects seemed to be attributable to the activation of the ganglionic α3β4 nAChR receptors, Abbott undertook a search for more selective α4β2 agonists, independently and in cooperation with Neurosearch.

a(MESH:"5-(2-azetidinylmethoxy)-2-chloropyridine") increases act(p(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

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a(MESH:"5-(2-azetidinylmethoxy)-2-chloropyridine") association path(MESH:Vomiting) View Subject | View Object

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a(MESH:"5-(2-azetidinylmethoxy)-2-chloropyridine") association path(MESH:Nausea) View Subject | View Object

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a(MESH:"5-(2-azetidinylmethoxy)-2-chloropyridine") increases act(complex(p(HGNC:CHRNA3), p(HGNC:CHRNB4))) View Subject | View Object

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path(MESH:Nausea) association a(MESH:"5-(2-azetidinylmethoxy)-2-chloropyridine") View Subject | View Object

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path(MESH:Vomiting) association a(MESH:"5-(2-azetidinylmethoxy)-2-chloropyridine") View Subject | View Object

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Evidence 1a1b0d62f1
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As expected, AR-R17779 — a selective partial alpha7 nAChR agonist — improved scopolamine-elicited deficits in social recognition, and the 24-hour memory retention interval in unimpaired animals. Repeated doses of AR-R17779 enhanced long-term learning and attenuated working-memory deficits in rats.

a(MESH:"AR-R 17779") increases bp(GO:learning) View Subject | View Object

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a(MESH:"AR-R 17779") increases bp(GO:memory) View Subject | View Object

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a(MESH:"AR-R 17779") decreases act(a(CHEBI:scopolamine)) View Subject | View Object

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Evidence 7878a39b05
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The nAChRs are ligand-gated ion channels that are present in both the PNS (at the skeletal neuromuscular junction and in the autonomic nervous system) and the CNS.

a(MESH:"Central Nervous System") association p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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a(MESH:"Peripheral Nervous System") association p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") association a(MESH:"Peripheral Nervous System") View Subject | View Object

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p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") association a(MESH:"Central Nervous System") View Subject | View Object

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Evidence 8071019ab9
JSON

Nicotine self administration is also reduced in rats by dihydro-beta erythroidine (DHbetae), a selective alpha4beta2 antagonist199. in this context, partial agonists may substitute for the desired effects of nicotine and antagonize its reinforcing properties163,200.

a(MESH:"Dihydro-beta-Erythroidine") decreases act(a(CHEBI:nicotine)) View Subject | View Object

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

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Evidence c4637cd989
JSON

For example, as discussed above, at least five functional nAChR subtypes have been identified in dopaminergic terminals in the striatum: α4α6β2β3, α6β2β3 and α6β2, which have the highest sensitivity to nicotine, and α4β2 and α4α5β2, which are more numerous than the α6-containing subtypes, yet with lower affinity for nicotine105,106,204.

a(MESH:"Dopaminergic Neurons") association complex(p(HGNC:CHRNA4), p(HGNC:CHRNA6), p(HGNC:CHRNB2), p(HGNC:CHRNB3)) View Subject | View Object

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Corpus Striatum
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Review

a(MESH:"Dopaminergic Neurons") association complex(p(HGNC:CHRNA6), p(HGNC:CHRNB2), p(HGNC:CHRNB3)) View Subject | View Object

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Corpus Striatum
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Review

a(MESH:"Dopaminergic Neurons") association complex(p(HGNC:CHRNA6), p(HGNC:CHRNB2)) View Subject | View Object

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Corpus Striatum
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Review

a(MESH:"Dopaminergic Neurons") association complex(p(HGNC:CHRNA4), p(HGNC:CHRNB2)) View Subject | View Object

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Corpus Striatum
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Review

a(MESH:"Dopaminergic Neurons") association complex(p(HGNC:CHRNA4), p(HGNC:CHRNA5), p(HGNC:CHRNB2)) View Subject | View Object

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Corpus Striatum
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complex(p(HGNC:CHRNA4), p(HGNC:CHRNA5), p(HGNC:CHRNB2)) association a(MESH:"Dopaminergic Neurons") View Subject | View Object

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Corpus Striatum
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complex(p(HGNC:CHRNA4), p(HGNC:CHRNA6), p(HGNC:CHRNB2), p(HGNC:CHRNB3)) association a(MESH:"Dopaminergic Neurons") View Subject | View Object

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Corpus Striatum
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Review

complex(p(HGNC:CHRNA4), p(HGNC:CHRNB2)) association a(MESH:"Dopaminergic Neurons") View Subject | View Object

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Corpus Striatum
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complex(p(HGNC:CHRNA6), p(HGNC:CHRNB2)) association a(MESH:"Dopaminergic Neurons") View Subject | View Object

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Corpus Striatum
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complex(p(HGNC:CHRNA6), p(HGNC:CHRNB2), p(HGNC:CHRNB3)) association a(MESH:"Dopaminergic Neurons") View Subject | View Object

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Corpus Striatum
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Evidence f9dca81a8c
JSON

General anaesthetics are small hydrophobic compounds that typically allosterically inhibit nAChRs by binding to specific residues within small cavities of the TMD61,62.

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

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Evidence a3a6a3d680
JSON

Regarding the ascending afferent excitatory pain pathway, in which nicotinic antagonists are anticipated to have analgesic effects, a newly described subtype of nAChR, α9α10, seems to be expressed on dorsal root ganglia (in addition to the inner ear) and constitutes an in vitro target for new α-conotoxins, such as vc1.1, RgiA, or it14a237–241.

a(MESH:Conotoxins) association complex(p(HGNC:CHRNA10), p(HGNC:CHRNA9)) View Subject | View Object

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complex(p(HGNC:CHRNA10), p(HGNC:CHRNA9)) association a(MESH:Conotoxins) View Subject | View Object

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Evidence 698c4ab0f9
JSON

In vivo, these α-conotoxins display potent alleviation of allopathic pain239,242,243 (and additionally reveal an endogeneous ACh activation of lymphocytes through α9α10 nAChRs, which are inhibited by these α-conotoxins).

a(MESH:Conotoxins) decreases act(complex(p(HGNC:CHRNA10), p(HGNC:CHRNA9))) View Subject | View Object

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a(MESH:Conotoxins) decreases path(MESH:Pain) View Subject | View Object

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complex(p(HGNC:CHRNA10), p(HGNC:CHRNA9)) increases act(a(MESH:Lymphocytes)) View Subject | View Object

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Evidence fff183fcbb
JSON

First, there is a high level of expression of alpha7 nAChRs in the hippocampus, a region that is known to be involved in memory formation. Second, gene knockout and antisense studies have shown a role for alpha7 nAChRs in learning and memory144–146, and specifically in attention and working–episodic memory147,148. Third, pharmacological studies have shown that a range of structurally diverse alpha7 nAChR-selective agonists or positive allosteric modulators improve the cognitive deficits that are associated with Alzheimer’s disease.

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

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a(MESH:Hippocampus) association bp(GO:memory) View Subject | View Object

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bp(GO:learning) association p(HGNC:CHRNA7) View Subject | View Object

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bp(GO:memory) association a(MESH:Hippocampus) View Subject | View Object

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bp(GO:memory) association p(HGNC:CHRNA7) View Subject | View Object

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

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MeSH
Alzheimer Disease
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p(HGNC:CHRNA7) association a(MESH:Hippocampus) View Subject | View Object

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p(HGNC:CHRNA7) association bp(GO:memory) View Subject | View Object

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p(HGNC:CHRNA7) association bp(GO:learning) View Subject | View Object

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Evidence 1f7292f5eb
JSON

The procognitive effect of MeM-3454 on episodic memory was completely blocked by the alpha7-specific antagonist methyllycaconitine, establishing that the efficacy of MeM-3454 can be attributed to alpha7 nAChR binding.

a(MESH:methyllycaconitine) decreases act(a(DRUGBANK:Facinicline)) View Subject | View Object

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Evidence eaa6e231be
JSON

in the cerebral cortex, the massive reduction in nAChRs in Alzheimer’s disease128–130 involves predominantly the alpha4beta2 subtype, sparing the alpha7 subtype131. By contrast, in the hippocampus, a loss of alpha7 nAChRs seems to predominate and to correlate with the progressive loss of cognitive function132–136.

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

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Hippocampus
MeSH
Alzheimer Disease
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p(HGNC:CHRNA7) positiveCorrelation bp(GO:cognition) View Subject | View Object

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

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Cerebral Cortex
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Evidence 8c5308955f
JSON

in addition to the obvious symptoms of hallucinations and delusions, patients with schizophrenia frequently suffer from cognitive symptoms, such as the inability to focus attention173.

bp(GO:cognition) association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Schizophrenia) association bp(GO:cognition) View Subject | View Object

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path(MESH:Delusions) association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Hallucinations) association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Schizophrenia) association path(MESH:Hallucinations) View Subject | View Object

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path(MESH:Schizophrenia) association path(MESH:Delusions) View Subject | View Object

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Evidence 4b8688d34e
JSON

nAChRs are known to control sensory gating, and studies investigating the role of nAChRs in schizophrenia have focused primarily on alpha7 nAChRs. Sensory-gating deficits in patients with schizophrenia174 have been linked to chromosome 15q14, proximal to the alpha7 locus175,176.

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

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p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") regulates bp(MESH:"Sensory Gating") View Subject | View Object

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

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Evidence 8e79a5378e
JSON

in addition, a decrease in alpha7 nAChR density in the hippocampus of patients with schizophrenia has been reported177. Similarly, a low density of alpha7 nAChRs in inbred strains of mice is associated with poor gating178. Recently, the expression of a novel variant of alpha7 nAChR, CHRNA7-2 (cholinergic receptor, nicotinic, alpha7, variant 2), was found to be reduced below control levels in the prefrontal cortex of patients with schizophrenia179.

bp(MESH:"Sensory Gating") association p(HGNC:CHRNA7) View Subject | View Object

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p(HGNC:CHRNA7) association bp(MESH:"Sensory Gating") View Subject | View Object

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path(MESH:Schizophrenia) decreases p(HGNC:CHRNA7) View Subject | View Object

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Hippocampus
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Evidence 2c9c9ce24a
JSON

β4 deletion abolishes withdrawal signs in the mouse208, and α3 and β4 are also present in the PNS, supporting the view that they might be directly involved in craving and relapse — an area that is largely unexplored in the development of medications to assist with smoking cessation.

p(HGNC:CHRNA3) association path(MESH:Craving) View Subject | View Object

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Corpus Striatum
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p(HGNC:CHRNA3) association path(MESH:Recurrence) View Subject | View Object

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Corpus Striatum
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p(HGNC:CHRNB4) association path(MESH:Craving) View Subject | View Object

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Corpus Striatum
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p(HGNC:CHRNB4) association path(MESH:Recurrence) View Subject | View Object

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Corpus Striatum
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path(MESH:Craving) association p(HGNC:CHRNA3) View Subject | View Object

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Corpus Striatum
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path(MESH:Craving) association p(HGNC:CHRNB4) View Subject | View Object

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Corpus Striatum
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Review

path(MESH:Recurrence) association p(HGNC:CHRNA3) View Subject | View Object

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Corpus Striatum
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path(MESH:Recurrence) association p(HGNC:CHRNB4) View Subject | View Object

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Corpus Striatum
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Evidence 7f5806b2d8
JSON

in α4- and β2-knockout mice, the responses of raphe neurons to nicotine is abolished, together with nicotine-elicited antinociception228, and α4-hypersensitive knock-in mice show nicotine hypersensitivity in the supraspinal control (hot-plate assay), but not in the spinal control (tail flick assay)229.

p(HGNC:CHRNA4) increases act(a(CHEBI:nicotine)) View Subject | View Object

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p(HGNC:CHRNB2) increases act(a(CHEBI:nicotine)) View Subject | View Object

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Evidence 462cb240e8
JSON

The cytoplasmic domain of the alpha4 nAChR subunit binds the scaffold protein 14-3-3η and the Ca2+ sensor visinin-like protein 1 (ReF. 69), and the beta2 subunit interacts with several cytoskeletal proteins, such as tubulin, dynamin and clathrin, and with G protein systems that are involved in intracellular signalling pathways70.

p(HGNC:CHRNB2) association p(HGNCGENEFAMILY:Tubulins) View Subject | View Object

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p(HGNC:CHRNB2) association p(HGNC:DNM1) View Subject | View Object

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p(HGNC:CHRNB2) association p(HGNCGENEFAMILY:"Clathrin subunits") View Subject | View Object

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p(HGNC:CHRNA4, frag("331_600")) association p(HGNC:YWHAH) View Subject | View Object

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p(HGNC:CHRNA4, frag("331_600")) association p(HGNC:VSNL1) View Subject | View Object

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p(HGNC:DNM1) association p(HGNC:CHRNB2) View Subject | View Object

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p(HGNC:VSNL1) association p(HGNC:CHRNA4, frag("331_600")) View Subject | View Object

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p(HGNC:YWHAH) association p(HGNC:CHRNA4, frag("331_600")) View Subject | View Object

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p(HGNCGENEFAMILY:"Clathrin subunits") association p(HGNC:CHRNB2) View Subject | View Object

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p(HGNCGENEFAMILY:Tubulins) association p(HGNC:CHRNB2) View Subject | View Object

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Evidence f543b7b18e
JSON

interestingly, three independent studies have mapped susceptibility loci for lung cancer at nAChR genes: CHRNA5, CHRNA3 and CHRNB4 (ReFS 205–207).

g(HGNC:CHRNA3) association path(MESH:"Lung Neoplasms") View Subject | View Object

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Corpus Striatum
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g(HGNC:CHRNA5) association path(MESH:"Lung Neoplasms") View Subject | View Object

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Corpus Striatum
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g(HGNC:CHRNB4) association path(MESH:"Lung Neoplasms") View Subject | View Object

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Corpus Striatum
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path(MESH:"Lung Neoplasms") association g(HGNC:CHRNA5) View Subject | View Object

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Corpus Striatum
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path(MESH:"Lung Neoplasms") association g(HGNC:CHRNA3) View Subject | View Object

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Corpus Striatum
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path(MESH:"Lung Neoplasms") association g(HGNC:CHRNB4) View Subject | View Object

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Corpus Striatum
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Evidence 5a1bc3ca32
JSON

ACh is produced by the enzyme choline acetyltransferase and its actions are mediated through two types of acetylcholine receptors (AChRs) — the G protein-coupled muscarinic AChRs and the nicotinic AChRs (nAChRs).

p(HGNC:CHAT) increases a(CHEBI:acetylcholine) View Subject | View Object

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

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

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Evidence 5db6619be5
JSON

By contrast, deleting the alpha7 nAChR subunit in a mouse model of Alzheimer’s disease that overexpresses a mutated form of the human amyloid precursor protein confers protection against memory loss and synaptic dysfunction, supporting a crucial role for alpha7 nAChR as a target288.

act(p(HGNC:CHRNA7)) decreases bp(GO:memory) View Subject | View Object

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Alzheimer Disease
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act(p(HGNC:CHRNA7)) decreases bp(MESH:Neuroprotection) View Subject | View Object

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Alzheimer Disease
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Evidence 286b1acbe9
JSON

Typically, activation of brain nAChRs results in enhanced release of various key neurotransmitters, including dopamine, serotonin, glutamate and GABA (gamma-aminobutyric acid).

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

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

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act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) increases sec(a(CHEBI:"glutamate(2-)")) View Subject | View Object

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

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Evidence 3f117d67bc
JSON

Alzheimer’s disease is characterized by progressive cognitive decline, accompanied by a loss of neurons and synapses — especially cholinergic synapses — in the basal forebrain, cerebral cortex and hippocampus126 and by a substantial reduction in both muscarinic and nicotinic AChR expression127.

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

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Basal Forebrain
MeSH
Cerebral Cortex
MeSH
Hippocampus
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path(MESH:"Alzheimer Disease") decreases a(MESH:Neurons) View Subject | View Object

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Basal Forebrain
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Cerebral Cortex
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Hippocampus
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path(MESH:"Alzheimer Disease") decreases p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") View Subject | View Object

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Basal Forebrain
MeSH
Cerebral Cortex
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Hippocampus
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path(MESH:"Alzheimer Disease") decreases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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Basal Forebrain
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Cerebral Cortex
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Hippocampus
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Evidence abf372136f
JSON

using in vivo proton NMR imaging, levels of choline (the rate-limiting precursor to endogeneous ACh) were shown to be increased in the brains of patients with depression217 and in the prefrontal cortex of adolescents with depression218 compared with the control group.

path(MESH:Depression) increases a(CHEBI:choline) View Subject | View Object

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Brain
MeSH
Prefrontal Cortex
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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.