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p(HBP:"alpha-4 beta-2 nAChR")

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Entity

Name
alpha-4 beta-2 nAChR
Namespace
HBP
Namespace Version
20181221
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/bd0996a28201cad363557315043c6392e31abf58/export/hbp-names.belns

Appears in Networks 3

albuquerque2009 v1.0.0

This file encodes the article Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function by Albuquerque et al, 2009

Neuronal Nicotinic Acetylcholine Receptor Structure and Function and Response to Nicotine v1.0.1

Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system v1.0.0

This document contains the curation of the review article Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system by Taly et al. 2009

In-Edges 25

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

Other studies have reported that alpha4beta2 nAChRs are more sensitive than alpha7 nAChRs to inhibition by nanomolar concentrations of Abeta1-42 (506). PubMed:19126755

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

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). PubMed:19126755

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

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. PubMed:19126755

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

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). PubMed:19126755

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

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). PubMed:19126755

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

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. PubMed:19126755

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

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. PubMed:19126755

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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

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. PubMed:19126755

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

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). PubMed:19126755

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

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). PubMed:19126755

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

Furthermore, TNF-alpha strongly promotes ligand-mediated upregulation of alpha4beta2 nAChRs through a mechanism that requires p38 mitogen-activated protein kinase (MAPK) signaling (163). PubMed:19126755

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

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). PubMed:19126755

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complex(a(CHEBI:epibatidine), p(HBP:"alpha-4 beta-2 nAChR")) hasComponent p(HBP:"alpha-4 beta-2 nAChR") 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

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). PubMed:19126755

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

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

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). PubMed:19126755

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

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). PubMed:19126755

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

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). PubMed:19126755

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

Most neuronal nAChRs, including alpha4beta2 and alpha7, are potentiated by Ca2+ at millimolar concentrations50. PubMed:19721446

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

in parallel, a voltage-dependent inhibitory Zn2+-binding site has been identified within the beta2 subunit of the alpha4beta2 nAChR48. PubMed:19721446

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

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). PubMed:19721446

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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

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. PubMed:19721446

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

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. PubMed:19721446

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

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. PubMed:19721446

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

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. PubMed:19721446

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MeSH
Cerebral Cortex
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Review

Out-Edges 9

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

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). PubMed:19126755

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

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). PubMed:19126755

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Review

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

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). PubMed:19126755

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

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). PubMed:19126755

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

A concurrent activation of preterminal alpha4beta2 nAChRs would hyperpolarize the neuron via GABAergic inhibition and prevent activation of the VGCC. PubMed:19126755

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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

A concurrent activation of preterminal alpha4beta2 nAChRs would hyperpolarize the neuron via GABAergic inhibition and prevent activation of the VGCC. PubMed:19126755

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

Activation of alpha4beta2 nAChRs on GABAergic interneurons in the VTA relieves the inhibitory control they exert on dopaminergic neurons (295, 380). PubMed:19126755

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

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). PubMed:19126755

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act(p(HBP:"alpha-4 beta-2 nAChR")) increases bp(GO:"depolarization of postsynaptic membrane") View Subject | View Object

Simultaneously, activity of postsynaptic (and somatic) α 4 β 2 * nAChRs depolarizes DA neurons leading to enhanced action potential firing (Zhang et al., 2009). PubMed:26472524

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Cell Ontology (CL)
dopaminergic neuron
MeSH
Post-Synaptic Density

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