CHRNA6
Cholinergic receptor, nicotinic, alpha 6, also known as nAChRα6, is a protein that in humans is encoded by the CHRNA6 gene.[5] The CHRNA6 gene codes for the α6 nicotinic receptor subunit that is found in certain types of nicotinic acetylcholine receptors found primarily in the brain. α6 subunits cannot form homomeric receptors. Instead, they form heteromeric receptors along with other alpha or beta subunits. Different combinations of subunits create receptors with unique pharmacology.[6]
Tissue distribution
[edit]α6-containing nicotinic acetylcholine receptors (nAChRs) show a restricted expression pattern in the brain. Neural nicotinic acetylcholine receptors containing α6 subunits are expressed on dopamine-releasing neurons in the midbrain.[7][8] α6 nAChRs are primarily expressed in three regions: the Ventral Tegmental Area (VTA) and the Substantia Nigra (SN), which are both part of the midbrain dopaminergic system, and the Locus Coeruleus (LC), located in the brainstem.[9]
Function
[edit]α6 nAChRs play a key role in regulating dopaminergic neurotransmission and respond to both nicotine and ethanol.
Nicotine
[edit]In the presence of nicotine, α6 nAChRs activate dopamine release in the VTA. This appears to take place through two mechanisms.
First, nicotine binds to α6 nAChRs on the axon terminals of presynaptic GABAergic neurons, which synapse onto postsynaptic dopaminergic neurons. Nicotine quickly desensitizes these receptors, preventing them from allowing Ca2+ to enter the axon terminal. Without Ca2+ to trigger neurotransmitter release, less GABA is released onto dopaminergic neurons. As a result, dopaminergic neurons are less inhibited, leading to more dopamine release.[10][11]
Second, nicotine binds to and activates α6 nAChRs on dopaminergic neurons. In the dendrites, this causes excitatory depolarization, increasing the dopaminergic cells' firing rate. At the axon terminals, this allows Ca2+ to enter, facilitating neurotransmitter release. Together, these effects cause dopaminergic neurons to release more dopamine.[9][12]
Dopamine release following activation of these neurons is thought to be involved in the addictive properties of nicotine.[13][14][15] Studies in mice show that knocking out the α6 subunit causes mice to stop self-administering nicotine, while reintroducing the subunit reverses this result.[16][17]
Ethanol
[edit]
In the VTA, low levels of ethanol increase dopamine release. Ethanol acts as a positive allosteric modulator by binding to α6 nAChRs on the axon terminals of GABAergic neurons outside the VTA, which connect to other GABAergic neurons within the VTA. ACh binding to these receptors causes Ca2+ influx into the upstream GABAergic neurons. Ethanol enhances this influx. This increases GABA release onto the VTA GABAergic neurons, inhibiting them and reducing their suppression of dopaminergic neurons. As a result, the dopaminergic neurons fire more rapidly, increasing dopamine release within the VTA[9][18]
However, very high levels of ethanol actually reduce dopamine release. The exact mechanism for this is unknown.[9][18]
In addition to nicotine, research in animals has implicated α6-containing nAChRs in the abusive and addictive properties of ethanol, with mecamylamine demonstrating a potent ability to block these properties.
Clinical significance
[edit]Because of their selective distribution and role in dopamine regulation in the Substantia Nigra, α6-containing receptors have been investigated as therapeutic targets. Due to their selective localisation on dopaminergic neurons, α6-containing nACh receptors have also been suggested as a possible therapeutic target for the treatment of Parkinson's disease.[19][20]
Interactive pathway map
[edit]Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ^ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602".
See also
[edit]References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000147434 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031491 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: CHRNA6 cholinergic receptor, nicotinic, alpha 6".
- ^ Papke RL, Dwoskin LP, Crooks PA, Zheng G, Zhang Z, McIntosh JM, et al. (June 2008). "Extending the analysis of nicotinic receptor antagonists with the study of alpha6 nicotinic receptor subunit chimeras". Neuropharmacology. 54 (8): 1189–1200. doi:10.1016/j.neuropharm.2008.03.010. PMC 2494738. PMID 18448138.
- ^ Le Novère N, Zoli M, Changeux JP (November 1996). "Neuronal nicotinic receptor alpha 6 subunit mRNA is selectively concentrated in catecholaminergic nuclei of the rat brain". The European Journal of Neuroscience. 8 (11): 2428–2439. doi:10.1111/j.1460-9568.1996.tb01206.x. PMID 8950106. S2CID 23102912.
- ^ Meyer EL, Yoshikami D, McIntosh JM (June 2008). "The neuronal nicotinic acetylcholine receptors alpha 4* and alpha 6* differentially modulate dopamine release in mouse striatal slices". Journal of Neurochemistry. 105 (5): 1761–1769. doi:10.1111/j.1471-4159.2008.05266.x. PMC 2527994. PMID 18248619.
- ^ a b c d Heydary YH, Castro EM, Lotfipour S, Leslie FM (March 2025). ""Unraveling the role of CHRNA6, the neuronal α6 nicotinic acetylcholine receptor subunit"". Receptors. 4 (1): 1. doi:10.3390/receptors4010001. PMC 12051391. PMID 40331132.
- ^ Quarta G, Stanzione R, Evangelista A, Zanda B, Di Angelantonio E, Marchitti S, et al. (November 2009). "Phosphodiesterase 4D and 5-lipoxygenase activating protein genes and risk of ischemic stroke in Sardinians". European Journal of Human Genetics. 17 (11): 1448–1453. doi:10.1038/aps.2009.63. PMC 2986684. PMID 19417766.
- ^ Ghoshal A, Tomarken A, Ebner F (February 2011). "Cross-sensory modulation of primary sensory cortex is developmentally regulated by early sensory experience". The Journal of Neuroscience. 31 (7): 2526–2536. doi:10.1523/JNEUROSCI.3003-10.2011. PMC 6623684. PMID 21325520.
- ^ Zylka MJ, Sowa NA, Taylor-Blake B, Twomey MA, Herrala A, Voikar V, et al. (October 2008). "Prostatic acid phosphatase is an ectonucleotidase and suppresses pain by generating adenosine". Neuron. 60 (1): 111–122. doi:10.1016/j.neuron.2008.09.009. PMC 2629077. PMID 18940592.
- ^ Calabresi P, Di Filippo M (October 2008). "ACh/dopamine crosstalk in motor control and reward: a crucial role for alpha 6-containing nicotinic receptors?". Neuron. 60 (1): 4–7. doi:10.1016/j.neuron.2008.09.031. PMID 18940582. S2CID 10537163.
- ^ Drenan RM, Grady SR, Whiteaker P, McClure-Begley T, McKinney S, Miwa JM, et al. (October 2008). "In vivo activation of midbrain dopamine neurons via sensitized, high-affinity alpha 6 nicotinic acetylcholine receptors". Neuron. 60 (1): 123–136. doi:10.1016/j.neuron.2008.09.009. PMC 2632732. PMID 18940593.
- ^ Exley R, Clements MA, Hartung H, McIntosh JM, Cragg SJ (August 2008). "Alpha6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine neurotransmission in nucleus accumbens". Neuropsychopharmacology. 33 (9): 2158–2166. doi:10.1038/sj.npp.1301617. PMID 18033235.
- ^ Guerrero A, Riddell SR, Storek J, Stevens-Ayers T, Storer B, Zaia JA, et al. (January 2012). "Cytomegalovirus viral load and virus-specific immune reconstitution after peripheral blood stem cell versus bone marrow transplantation". Biology of Blood and Marrow Transplantation. 18 (1): 66–75. doi:10.1016/j.bcp.2011.06.001. PMC 3237869. PMID 21664286.
- ^ Benali A, Weiler E, Benali Y, Dinse HR, Eysel UT (November 2008). "Excitation and inhibition jointly regulate cortical reorganization in adult rats". The Journal of Neuroscience. 28 (47): 12284–12293. doi:10.1523/JNEUROSCI.3918-08.2008. PMC 6671719. PMID 19020022.
- ^ a b Akhoundi MS, Etemadi A, Nasiri M, Borujeni ES (May 2017). "Comparison of Enamel Morphologic Characteristics after Conditioning with Various Combinations of Acid Etchant and Er:YAG Laser in Bonding and Rebonding Procedures: A SEM Analysis". Journal of Dentistry. 14 (3): 144–152. doi:10.1111/adb.12559. PMC 5694847. PMID 29167686.
- ^ Quik M, McIntosh JM (February 2006). "Striatal alpha6* nicotinic acetylcholine receptors: potential targets for Parkinson's disease therapy". The Journal of Pharmacology and Experimental Therapeutics. 316 (2): 481–489. doi:10.1124/jpet.105.094375. PMID 16210393. S2CID 20050682.
- ^ Bordia T, Grady SR, McIntosh JM, Quik M (July 2007). "Nigrostriatal damage preferentially decreases a subpopulation of alpha6beta2* nAChRs in mouse, monkey, and Parkinson's disease striatum". Molecular Pharmacology. 72 (1): 52–61. doi:10.1124/mol.107.035998. PMID 17409284. S2CID 25281990.
Further reading
[edit]- Zeiger JS, Haberstick BC, Schlaepfer I, Collins AC, Corley RP, Crowley TJ, et al. (March 2008). "The neuronal nicotinic receptor subunit genes (CHRNA6 and CHRNB3) are associated with subjective responses to tobacco". Human Molecular Genetics. 17 (5): 724–734. doi:10.1093/hmg/ddm344. PMID 18055561.
- Shi J, Hattori E, Zou H, Badner JA, Christian SL, Gershon ES, et al. (September 2007). "No evidence for association between 19 cholinergic genes and bipolar disorder". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 144B (6): 715–723. doi:10.1002/ajmg.b.30417. PMC 2576477. PMID 17373692.
- Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, et al. (November 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–648. doi:10.1016/j.cell.2006.09.026. PMID 17081983. S2CID 7827573.
- Keiger CJ, Case LD, Kendal-Reed M, Jones KR, Drake AF, Walker JC (January 2003). "Nicotinic cholinergic receptor expression in the human nasal mucosa". The Annals of Otology, Rhinology, and Laryngology. 112 (1): 77–84. doi:10.1177/000348940311200115. PMID 12537063. S2CID 24705718.
- Ebihara M, Ohba H, Ohno SI, Yoshikawa T (September 2002). "Genomic organization and promoter analysis of the human nicotinic acetylcholine receptor alpha6 subunit (CHNRA6) gene: Alu and other elements direct transcriptional repression". Gene. 298 (1): 101–108. doi:10.1016/S0378-1119(02)00925-3. PMID 12406580.
- Graham A, Court JA, Martin-Ruiz CM, Jaros E, Perry R, Volsen SG, et al. (2002). "Immunohistochemical localisation of nicotinic acetylcholine receptor subunits in human cerebellum". Neuroscience. 113 (3): 493–507. doi:10.1016/S0306-4522(02)00223-3. PMID 12150770. S2CID 39839166.
- Elliott KJ, Ellis SB, Berckhan KJ, Urrutia A, Chavez-Noriega LE, Johnson EC, et al. (1997). "Comparative structure of human neuronal alpha 2-alpha 7 and beta 2-beta 4 nicotinic acetylcholine receptor subunits and functional expression of the alpha 2, alpha 3, alpha 4, alpha 7, beta 2, and beta 4 subunits". Journal of Molecular Neuroscience. 7 (3): 217–228. doi:10.1007/BF02736842. PMID 8906617. S2CID 45737923.
External links
[edit]- CHRNA6+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Human CHRNA6 genome location and CHRNA6 gene details page in the UCSC Genome Browser.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.