p(HBP:"alpha-4 beta-2 nAChR")
Other studies have reported that alpha4beta2 nAChRs are more sensitive than alpha7 nAChRs to inhibition by nanomolar concentrations of Abeta1-42 (506). PubMed:19126755
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Most neuronal nAChRs, including alpha4beta2 and alpha7, are potentiated by Ca2+ at millimolar concentrations50. PubMed:19721446
in parallel, a voltage-dependent inhibitory Zn2+-binding site has been identified within the beta2 subunit of the alpha4beta2 nAChR48. PubMed:19721446
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
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
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
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
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
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
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
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
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
A concurrent activation of preterminal alpha4beta2 nAChRs would hyperpolarize the neuron via GABAergic inhibition and prevent activation of the VGCC. PubMed:19126755
A concurrent activation of preterminal alpha4beta2 nAChRs would hyperpolarize the neuron via GABAergic inhibition and prevent activation of the VGCC. PubMed:19126755
Activation of alpha4beta2 nAChRs on GABAergic interneurons in the VTA relieves the inhibitory control they exert on dopaminergic neurons (295, 380). PubMed:19126755
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
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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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.