The neuronal acetylcholine receptor subunit alpha-5, or alpha-5 nicotinic acetylcholine receptor (
Neuronal acetylcholine receptor subunit alpha-5 | |||||||
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Identifiers | |||||||
Symbol | CHRNA5 | ||||||
Alt. symbols | CHRNA5 | ||||||
NCBI gene | 1138 | ||||||
OMIM | 1188505 | ||||||
RefSeq | NM_000745 | ||||||
UniProt | P30532 | ||||||
Other data | |||||||
Locus | Chr. 15 q25.1 | ||||||
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Overview
editThere are two major classes of acetylcholine receptors: nicotinic receptors, which bind to exogenous nicotine, and muscarinic receptors, which bind exogenous muscarine. Nicotinic acetylcholine receptors (nAChRs) were initially discovered through the application and binding of nicotine, however, endogenous acetylcholine is the ligand that binds under normal physiological conditions. The nAChRs are single channel ionotropic receptors found throughout the brain and body that allow for cations to flow in and out of cells. These receptors consist of five transmembrane subunits with the
Development
editThe alpha5 subunit is important during the development and maturation of prefrontal pyramidal IV neurons. Cholinergic dysfunction during development causes attentional deficits observed in diseases such as schizophrenia, neurodevelopmental disorders, autism and epilepsy. Most cholinergic neurons are developed by the perinatal period in humans. Maturational changes that occur in dendrites during development are absent in alpha5 -/- mice indicating that the alpha5 subunit is necessary for proper maturation of prefrontal pyramidal cells.[5]
Nicotine addiction and withdrawal
editAddiction 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
In vivo studies
editStudies have shown that removing the
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
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
editNicotine 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
Attention and cognition
editAttention 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
editResearchers speculate that layer VI pyramidal neurons in the prefrontal cortex are important for holding attention in cognitively demanding tasks. These neurons send feedback projections to the thalamus and are highly responsive to acetylcholine. In vivo studies have shown that the presence of alpha5 subunits of nAChRs on layer VI pyramidal neurons in the PFC are important for visual attention.[21] In slice electrophysiology experiments, researchers have shown that alpha5 subunits enhance currents in the PFC of an adult mouse. In vivo, researchers use a five-choice serial reaction task. The animals are randomly given 1 of 5 light stimulus, and they need to encode and recall the location of the stimulus in order to receive a reward. Transgenic mice without the gene that encodes alpha5 subunits showed impaired performance on the five-choice serial reaction task. This indicates that the alpha5 null mice have attentional deficits.[5] Interestingly, the deletion of alpha5 subunits in mice results in an upregulation of muscarinic acetylcholine receptors as an excitatory compensation response to circuitry dysfunction. Because of the cognitive enhancing effects of alpha5 nAChR agonists, it is a common target for neurodegenerative disorders with cognitive deficits along with ADHD.[22]
Human studies
editDue 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
editThe
Ligands
editLigand | 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] | |
Antagonist | |||
Antagonist | |||
Antagonist | |||
Antagonist |
Interactive pathway map
editClick on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ^ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602".
References
edit- ^ Brown RW, Collins AC, Lindstrom JM, Whiteaker P (October 2007). "Nicotinic alpha5 subunit deletion locally reduces high-affinity agonist activation without altering nicotinic receptor numbers". Journal of Neurochemistry. 103 (1): 204–215. doi:10.1111/j.1471-4159.2007.04700.x. PMID 17573823. S2CID 28394031.
- ^ Bagdas D, AlSharari SD, Freitas K, Tracy M, Damaj MI (October 2015). "The role of alpha5 nicotinic acetylcholine receptors in mouse models of chronic inflammatory and neuropathic pain". Biochemical Pharmacology. Nicotinic Acetylcholine Receptors as Therapeutic Targets: Emerging Frontiers in Basic Research and Clinical Science (Satellite to the 2015 Meeting of the Society for Neuroscience) Oct 14-15, Chicago, IL USA. 97 (4): 590–600. doi:10.1016/j.bcp.2015.04.013. PMC 4600420. PMID 25931144.
- ^ Brown RW, Collins AC, Lindstrom JM, Whiteaker P (October 2007). "Nicotinic alpha5 subunit deletion locally reduces high-affinity agonist activation without altering nicotinic receptor numbers". Journal of Neurochemistry. 103 (1): 204–215. doi:10.1111/j.1471-4159.2007.04700.x. PMID 17573823. S2CID 28394031.
- ^ a b c Greenbaum L, Lerer B (October 2009). "Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions". Molecular Psychiatry. 14 (10): 912–945. doi:10.1038/mp.2009.59. PMID 19564872. S2CID 9769700.
- ^ a b c Proulx E, Piva M, Tian MK, Bailey CD, Lambe EK (April 2014). "Nicotinic acetylcholine receptors in attention circuitry: the role of layer VI neurons of prefrontal cortex". Cellular and Molecular Life Sciences. 71 (7): 1225–1244. doi:10.1007/s00018-013-1481-3. PMC 3949016. PMID 24122021.
- ^ de Kloet SF, Mansvelder HD, De Vries TJ (October 2015). "Cholinergic modulation of dopamine pathways through nicotinic acetylcholine receptors". Biochemical Pharmacology. 97 (4): 425–438. doi:10.1016/j.bcp.2015.07.014. PMID 26208783.
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- ^ Antolin-Fontes B, Ables JL, Görlich A, Ibañez-Tallon I (September 2015). "The habenulo-interpeduncular pathway in nicotine aversion and withdrawal". Neuropharmacology. 96 (Pt B): 213–222. doi:10.1016/j.neuropharm.2014.11.019. PMC 4452453. PMID 25476971.
- ^ a b c d e De Biasi M, Dani JA (2011-07-21). "Reward, addiction, withdrawal to nicotine". Annual Review of Neuroscience. 34 (1): 105–130. doi:10.1146/annurev-neuro-061010-113734. PMC 3137256. PMID 21438686.
- ^ a b c d e f Tuesta LM, Fowler CD, Kenny PJ (October 2011). "Recent advances in understanding nicotinic receptor signaling mechanisms that regulate drug self-administration behavior". Biochemical Pharmacology. 82 (8): 984–995. doi:10.1016/j.bcp.2011.06.026. PMC 3163076. PMID 21740894.
- ^ a b Stoker AK, Markou A (August 2013). "Unraveling the neurobiology of nicotine dependence using genetically engineered mice". Current Opinion in Neurobiology. 23 (4): 493–499. doi:10.1016/j.conb.2013.02.013. PMC 3735838. PMID 23545467.
- ^ De Biasi M, Dani JA (2011-07-21). "Reward, addiction, withdrawal to nicotine". Annual Review of Neuroscience. 34 (1): 105–130. doi:10.1146/annurev-neuro-061010-113734. PMC 3137256. PMID 21438686.
- ^ Improgo MR, Scofield MD, Tapper AR, Gardner PD (September 2010). "From smoking to lung cancer: the CHRNA5/A3/B4 connection". Oncogene. 29 (35): 4874–4884. doi:10.1038/onc.2010.256. PMC 3934347. PMID 20581870.
- ^ Improgo MR, Scofield MD, Tapper AR, Gardner PD (October 2010). "The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: dual role in nicotine addiction and lung cancer". Progress in Neurobiology. 92 (2): 212–226. doi:10.1016/j.pneurobio.2010.05.003. PMC 2939268. PMID 20685379.
- ^ Russo P, Cesario A, Rutella S, Veronesi G, Spaggiari L, Galetta D, et al. (2010-12-31). "Impact of genetic variability in nicotinic acetylcholine receptors on nicotine addiction and smoking cessation treatment". Current Medicinal Chemistry. 18 (1): 91–112. doi:10.2174/092986711793979715. PMID 21110812.
- ^ Greenbaum L, Lerer B (October 2009). "Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions". Molecular Psychiatry. 14 (10): 912–945. doi:10.1038/mp.2009.59. PMID 19564872. S2CID 9769700.
- ^ Ware JJ, van den Bree M, Munafò MR (November 2012). "From men to mice: CHRNA5/CHRNA3, smoking behavior and disease". Nicotine & Tobacco Research. 14 (11): 1291–1299. doi:10.1093/ntr/nts106. PMC 3482013. PMID 22544838.
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- ^ Salas R, Orr-Urtreger A, Broide RS, Beaudet A, Paylor R, De Biasi M (May 2003). "The nicotinic acetylcholine receptor subunit alpha 5 mediates short-term effects of nicotine in vivo". Molecular Pharmacology. 63 (5): 1059–1066. doi:10.1124/mol.63.5.1059. PMID 12695534. S2CID 97775995.
- ^ a b Fowler CD, Lu Q, Johnson PM, Marks MJ, Kenny PJ (March 2011). "Habenular
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- ^ Decker MW, Meyer MD, Sullivan JP (October 2001). "The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control". Expert Opinion on Investigational Drugs. 10 (10): 1819–1830. doi:10.1517/13543784.10.10.1819. PMID 11772288. S2CID 24924290.
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