| CACNA1A | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | CACNA1A, APCA, BI, CACNL1A4, CAV2.1, EA2, FHM, HPCA, MHP, MHP1, SCA6, Cav2.1, calcium voltage-gated channel subunit alpha1 A, EIEE42, DEE42 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 601011 MGI: 109482 HomoloGene: 56383 GeneCards: CACNA1A | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Cav2.1, also called the P/Q voltage-dependent calcium channel, is a calcium channel found mainly in the brain.[5] Specifically, it is found on the presynaptic terminals of neurons in the brain and cerebellum.[5] Cav2.1 plays an important role in controlling the release of neurotransmitters between neurons.[5] It is composed of multiple subunits, including alpha-1, beta, alpha-2/delta, and gamma subunits.[6] The alpha-1 subunit is the pore-forming subunit, meaning that the calcium ions flow through it.[6] Different kinds of calcium channels have different isoforms (versions) of the alpha-1 subunit. Cav2.1 has the alpha-1A subunit,[6] which is encoded by the CACNA1A gene.[lower-alpha 1][5] Mutations in CACNA1A have been associated with various neurologic disorders, including familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6.[5]
Function
"Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue."[6]
Clinical significance
Mutations in the CACNA1A gene are associated with multiple neurologic disorders, many of which are episodic, such as familial hemiplegic migraine, movement disorders such as episodic ataxia, and epilepsy with multiple seizure types.[8]
"This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. However, in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-16 to 21-28 in the coding region is associated with spinocerebellar ataxia 6."[6]
Interactions
Notes
References
- 1 2 3 GRCh38: Ensembl release 89: ENSG00000141837 - Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000034656 - 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.
- 1 2 3 4 5 Sutherland HG, Albury CL, Griffiths LR (21 June 2019). "Advances in genetics of migraine". The Journal of Headache and Pain. 20 (1): 72. doi:10.1186/s10194-019-1017-9. PMC 6734342. PMID 31226929.
- 1 2 3 4 5 "CACNA1A". Gene. National Center for Biotechnology Information. 16 March 2021. Retrieved 28 March 2021.
- ↑ "The Science of CACNA1A". CACNA1A Foundation. Retrieved 28 March 2021.
- ↑ Papandreou A, Danti FR, Spaull R, Leuzzi V, Mctague A, Kurian MA (February 2020). "The expanding spectrum of movement disorders in genetic epilepsies". Developmental Medicine and Child Neurology. 62 (2): 178–191. doi:10.1111/dmcn.14407. PMID 31784983. S2CID 208498567.
- ↑ Walker D, Bichet D, Campbell KP, De Waard M (January 1998). "A beta 4 isoform-specific interaction site in the carboxyl-terminal region of the voltage-dependent Ca2+ channel alpha 1A subunit". The Journal of Biological Chemistry. 273 (4): 2361–7. doi:10.1074/jbc.273.4.2361. PMID 9442082.
- ↑ Walker D, Bichet D, Geib S, Mori E, Cornet V, Snutch TP, et al. (April 1999). "A new beta subtype-specific interaction in alpha1A subunit controls P/Q-type Ca2+ channel activation". The Journal of Biological Chemistry. 274 (18): 12383–90. doi:10.1074/jbc.274.18.12383. PMID 10212211.
Further reading
- Terwindt G, Kors E, Haan J, Vermeulen F, Van den Maagdenberg A, Frants R, Ferrari M (June 2002). "Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine". Archives of Neurology. 59 (6): 1016–8. doi:10.1001/archneur.59.6.1016. PMID 12056940.
- Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (December 2005). "International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels". Pharmacological Reviews. 57 (4): 411–25. doi:10.1124/pr.57.4.5. PMID 16382099. S2CID 10386627.
- Perez-Reyes E, Castellano A, Kim HS, Bertrand P, Baggstrom E, Lacerda AE, et al. (January 1992). "Cloning and expression of a cardiac/brain beta subunit of the L-type calcium channel". The Journal of Biological Chemistry. 267 (3): 1792–7. doi:10.1016/S0021-9258(18)46015-2. PMID 1370480.
- Barry EL, Viglione MP, Kim YI, Froehner SC (January 1995). "Expression and antibody inhibition of P-type calcium channels in human small-cell lung carcinoma cells". The Journal of Neuroscience. 15 (1 Pt 1): 274–83. doi:10.1523/JNEUROSCI.15-01-00274.1995. PMC 6578292. PMID 7823133.
- Joutel A, Bousser MG, Biousse V, Labauge P, Chabriat H, Nibbio A, et al. (September 1993). "A gene for familial hemiplegic migraine maps to chromosome 19". Nature Genetics. 5 (1): 40–5. doi:10.1038/ng0993-40. PMID 8220421. S2CID 6493091.
- Margolis RL, Breschel TS, Li SH, Kidwai AS, Antonarakis SE, McInnis MG, Ross CA (July 1995). "Characterization of cDNA clones containing CCA trinucleotide repeats derived from human brain". Somatic Cell and Molecular Genetics. 21 (4): 279–84. doi:10.1007/BF02255782. PMID 8525433. S2CID 22174220.
- Rettig J, Sheng ZH, Kim DK, Hodson CD, Snutch TP, Catterall WA (July 1996). "Isoform-specific interaction of the alpha1A subunits of brain Ca2+ channels with the presynaptic proteins syntaxin and SNAP-25". Proceedings of the National Academy of Sciences of the United States of America. 93 (14): 7363–8. Bibcode:1996PNAS...93.7363R. doi:10.1073/pnas.93.14.7363. PMC 38990. PMID 8692999.
- Diriong S, Lory P, Williams ME, Ellis SB, Harpold MM, Taviaux S (December 1995). "Chromosomal localization of the human genes for alpha 1A, alpha 1B, and alpha 1E voltage-dependent Ca2+ channel subunits". Genomics. 30 (3): 605–9. doi:10.1006/geno.1995.1284. PMID 8825650.
- Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, et al. (November 1996). "Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4". Cell. 87 (3): 543–52. doi:10.1016/S0092-8674(00)81373-2. hdl:1765/57576. PMID 8898206. S2CID 16840573.
- Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, et al. (January 1997). "Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel". Nature Genetics. 15 (1): 62–9. doi:10.1038/ng0197-62. PMID 8988170. S2CID 9116828.
- De Waard M, Liu H, Walker D, Scott VE, Gurnett CA, Campbell KP (January 1997). "Direct binding of G-protein betagamma complex to voltage-dependent calcium channels". Nature. 385 (6615): 446–50. doi:10.1038/385446a0. PMID 9009193. S2CID 4287544.
- Qin N, Platano D, Olcese R, Stefani E, Birnbaumer L (August 1997). "Direct interaction of gbetagamma with a C-terminal gbetagamma-binding domain of the Ca2+ channel alpha1 subunit is responsible for channel inhibition by G protein-coupled receptors". Proceedings of the National Academy of Sciences of the United States of America. 94 (16): 8866–71. doi:10.1073/pnas.94.16.8866. PMC 23172. PMID 9238069.
- Riess O, Schöls L, Bottger H, Nolte D, Vieira-Saecker AM, Schimming C, et al. (August 1997). "SCA6 is caused by moderate CAG expansion in the alpha1A-voltage-dependent calcium channel gene". Human Molecular Genetics. 6 (8): 1289–93. doi:10.1093/hmg/6.8.1289. PMID 9259275.
- Jodice C, Mantuano E, Veneziano L, Trettel F, Sabbadini G, Calandriello L, et al. (October 1997). "Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p". Human Molecular Genetics. 6 (11): 1973–8. doi:10.1093/hmg/6.11.1973. hdl:2108/35797. PMID 9302278.
- Charvin N, L'evêque C, Walker D, Berton F, Raymond C, Kataoka M, et al. (August 1997). "Direct interaction of the calcium sensor protein synaptotagmin I with a cytoplasmic domain of the alpha1A subunit of the P/Q-type calcium channel". The EMBO Journal. 16 (15): 4591–6. doi:10.1093/emboj/16.15.4591. PMC 1170085. PMID 9303303.
- Ishikawa K, Tanaka H, Saito M, Ohkoshi N, Fujita T, Yoshizawa K, et al. (August 1997). "Japanese families with autosomal dominant pure cerebellar ataxia map to chromosome 19p13.1-p13.2 and are strongly associated with mild CAG expansions in the spinocerebellar ataxia type 6 gene in chromosome 19p13.1". American Journal of Human Genetics. 61 (2): 336–46. doi:10.1086/514867. PMC 1715894. PMID 9311738.
- Walker D, Bichet D, Campbell KP, De Waard M (January 1998). "A beta 4 isoform-specific interaction site in the carboxyl-terminal region of the voltage-dependent Ca2+ channel alpha 1A subunit". The Journal of Biological Chemistry. 273 (4): 2361–7. doi:10.1074/jbc.273.4.2361. PMID 9442082.
- Yue Q, Jen JC, Thwe MM, Nelson SF, Baloh RW (May 1998). "De novo mutation in CACNA1A caused acetazolamide-responsive episodic ataxia". American Journal of Medical Genetics. 77 (4): 298–301. doi:10.1002/(SICI)1096-8628(19980526)77:4<298::AID-AJMG9>3.0.CO;2-J. PMID 9600739.
- Hans M, Urrutia A, Deal C, Brust PF, Stauderman K, Ellis SB, et al. (March 1999). "Structural elements in domain IV that influence biophysical and pharmacological properties of human alpha1A-containing high-voltage-activated calcium channels". Biophysical Journal. 76 (3): 1384–400. doi:10.1016/S0006-3495(99)77300-5. PMC 1300117. PMID 10049321.
- Walker D, Bichet D, Geib S, Mori E, Cornet V, Snutch TP, et al. (April 1999). "A new beta subtype-specific interaction in alpha1A subunit controls P/Q-type Ca2+ channel activation". The Journal of Biological Chemistry. 274 (18): 12383–90. doi:10.1074/jbc.274.18.12383. PMID 10212211.
- Nikonishyna YV, et al. (2022). "Novel CACNA1A Variant p.Cys256Phe Disrupts Disulfide Bonds and Causes Spinocerebellar Ataxia". Movement Disorders. Movement disorders: official journal of the Movement Disorder Society. 37 (2): 401–404. doi:10.1002/mds.28835. PMID 34647648. S2CID 238859984.
Further reading
- Jen JC (May 2015) [1993]. "Familial Hemiplegic Migraine". In Pagon RA, Bird TD, Dolan CR, et al. (eds.). GeneReviews. Seattle WA: University of Washington, Seattle. NBK1388.
- Spacey S (December 2011). "Episodic Ataxia Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY". Episodic Ataxia Type 2. University of Washington, Seattle. PMID 20301674. NBK1501.
{{cite book}}: CS1 maint: overridden setting (link) In GeneReviews - Gomez CM (July 2013). Spinocerebellar Ataxia Type 6. University of Washington, Seattle. PMID 20301319. NBK1140.
{{cite book}}: CS1 maint: overridden setting (link) In GeneReviews
- CACNA1A+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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