Neuronal acetylcholine receptor subunit alpha-5
Neuronal acetylcholine receptor subunit alpha-5 | |||||||
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Identifiers | |||||||
Symbol | CHRNA5 | ||||||
Alt. symbols | CHRNA5 | ||||||
Chr. 15 q25.1 | |||||||
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The neuronal acetylcholine receptor subunit alpha-5, or alpha-5 nicotinic acetylcholine receptor (α5 nAChR) also known as the α5 receptor is a type of ligand gated neuronal type subunit of the nicotinic acetylcholine receptor involved in pain regulation encoded in the human by the CHRNA5 gene. This receptor is commonly associated with nicotine addiction, immunotherapy, cancer, pain and attention.
Overview
There are two major classes of
Development
The alpha5 subunit is important during the
Nicotine addiction and withdrawal
Addiction to nicotine is modulated by the mesocorticolimbic dopamine reward system that drives the rewarding nature of nicotine; the mesocorticolimbic system is involved in self-stimulation and processing an environmental reward.[6][7] For example, this system is active while consuming highly caloric food or while gambling. Upon the administration of nicotine, there is increased firing rate mediated by midbrain dopamine neurons within this system. Through continuous exposure, dependence often occurs which is followed by withdrawal symptoms such as cravings, irritation, restlessness, sleep disturbances, weight gain, anxiety and difficulty concentrating.[8][9] Subunits involved with withdrawal syndrome include α5, α2, and B4 within the epithalamic habenular complex and its projections.[10] The medial habenula (MHb) and its projection to the interpeduncular nucleus (IPN) contain dense expression of α5 nAChR subunits.[11]
In vivo studies
Studies have shown that removing the α5 nAChR subunits from mice (α5 nAChR null) will make them less sensitive to acute effects of nicotine.[12] The mice showed decreased locomotion in an open field test and fewer nicotine-induced seizures.[11] Other studies have shown that α5 nAChR null mice display fewer signs of dependency and reduced anxiety-like behaviors.[11] Because the knockout mice show less aversion to increased nicotine intake, they tend to self-administer at much higher doses than wildtype mice. However, reintroduction of the alpha 5 subunit in the medial habenula in knockout mice restored normal levels of nicotine self-administration. This demonstrates that the expression of the alpha5 subunit in the medial habenula is sufficient to reinstate nicotine aversion.[13] In contrast, the targeted knockdown of α5 subunits in the habenulo-interpeduncular pathway in wildtype mice did not change the stimulatory effects observed in knockout mice demonstrating that the subunit is not necessary for nicotine aversion, and that other areas of the brain can compensate for this behavior.[12]
In a conditioned place preference study (CPP), researchers trained mice to associate nicotine administration with one chamber and saline administration in an adjacent chamber. At low doses of nicotine, alpha5 knockout mice and wildtype mice both showed preference for the nicotine chamber. However, at high doses of nicotine, only the α5 knockout mice preferred the nicotine chamber[13] demonstrating that the alpha5 knockout mice still experienced the rewarding aspects of nicotine, but not the normal aversive behaviors with nicotine overdose.
Studies from Tuesta et al. 2011 have shown that the dose-response curve is similar when comparing knockout mice to wildtype mice however the knockout mice consumed greater amounts of nicotine which resulted in the descending portion of the dose-response curve to descend declined slower in the knockout mice. There has been shown an increased response to nicotine in the ascending portion of the curve demonstrating the greater rewarding properties.[12]
Human studies
Nicotine is commonly consumed by people for its rewarding properties resulting in dependence, addiction and withdrawal.[14] Human studies have shown that people with a single nucleotide polymorphism (SNP) within the α5 nAChR encoding gene (CHRNA5, rs16969968) correlates with an increased risk of nicotine dependency and pleasure along with more heavy smoking.[11][15][16][17] This particular SNP results in an aspartic acid to asparagine substitution at amino acid residue 398 (D398N).[12] The rs16969968 within CHRNA5 causes a reduction in the receptor function that is involved in producing withdrawal symptoms. Individuals with this SNP are commonly found in those of European descent; there is about a 30% greater risk of nicotine dependence in individuals carry a single copy of the variant and about a 50% greater risk in individuals with two copies.[12] Other studies have shown that people with this SNP develop nicotine dependence at a younger age.[12] Researchers conclude that fewer aversive effects of nicotine would promote the rewarding effects or hedonic drive that would transition people from nicotine abuse to dependency.[11][18] Additionally, SNP variants within rs16969968 in CHRNA5 have been associated with smoking-related behaviors such has a higher prevalence of smokers vs nonsmokers.[19]
Attention and cognition
Attention is an important aspect of memory that allows for information to be held in the mind and maintain focus in the presence of distractions in order to achieve a goal directed behavior. Working memory is a similar aspect of learning, however, the main difference between the two is that working memory requires the mental manipulation of information as well. The structure most commonly associated with attention is the prefrontal cortex that mediates top down control of complex cognitive processes.[20] Acetylcholine is a neuromodulator that is closely studied for its role in learning and memory; it is involved in the acquisition, consolidation and recall.
In vivo studies
Researchers speculate that layer VI
Human studies
Due to technical limitations of invasive procedures, there are far fewer studies in about the role of the alpha5 nAChR subunit and cognition. Studies have performed microdialysis in subjects as they formed attention tasks and found significantly increased acetylcholine efflux.[5]
Clinical application
The α5 nAChR mediates acute effects of alcohol; a deletion in this gene affects alcohol intake under stressful conditions.[23] The α5 nAChR also mediates short term effects of nicotine.[24] Studies have shown that removing the alpha5 subunit in mice (α5 nAChR knockdown) increases nicotine intake which is rescued by reintroducing the gene.[25] Researchers have also shown that removing the α5 subunit only in the medial habenula increases nicotine self-administration, demonstrating that this subunit is necessary for normal nicotine intake and abnormalities within this subunit may contribute to the addictive properties of nicotine.[25] Additionally, the alpha5 nAChR subunit is associated with other forms of addiction such as cocaine.[26] Other studies have shown that α5 knockout mice shown impaired attentional performance.[27] During high frequency vagal stimulation, α5 nAChR knockout mice experience impaired cardiac parasympathetic ganglionic transmission. In vivo studies have also identified the alpha5 nAChR as a possible treatment for chronic inflammation and neuropathic pain.[28][29]
Ligands
Ligand | Structure | Function | Use |
---|---|---|---|
Acetylcholine | Agonist | Endogenous | |
Nicotine | Agonist | Recreational drug Attention | |
Pozanicline | Partial agonist | Experimental drug for ADHD, [30] Alzheimer's disease,[31] and tobacco use disorder[32] | |
α-Conotoxin MII[33] | Antagonist | ||
α-Conotoxin PnIA[33] | Antagonist | ||
α-Conotoxin GIC[33] | Antagonist | ||
α-Conotoxin TXIA[33] | Antagonist |
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ^ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602".
References
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