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.
Clinical significance
Mutations in this gene are associated with neurologic disorders, including familial hemiplegic migraine and episodic ataxia 2.
This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants have been described, however, the full-length nature of not all is known. 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.[5]
^Walker D, Bichet D, Campbell KP, De Waard M (Jan 1998). "A beta 4 isoform-specific interaction site in the carboxyl-terminal region of the voltage-dependent Ca2+ channel alpha 1A subunit". J. Biol. Chem. 273 (4): 2361–7. doi:10.1074/jbc.273.4.2361. PMID9442082.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^Walker D, Bichet D, Geib S, Mori E, Cornet V, Snutch TP, Mori Y, De Waard M (Apr 1999). "A new beta subtype-specific interaction in alpha1A subunit controls P/Q-type Ca2+ channel activation". J. Biol. Chem. 274 (18): 12383–90. doi:10.1074/jbc.274.18.12383. PMID10212211.{{cite journal}}: CS1 maint: unflagged free DOI (link)
Further reading
Terwindt G, Kors E, Haan J, Vermeulen F, Van den Maagdenberg A, Frants R, Ferrari M (2002). "Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine". Arch. Neurol. 59 (6): 1016–8. doi:10.1001/archneur.59.6.1016. PMID12056940.
Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (2005). "International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels". Pharmacol. Rev. 57 (4): 411–25. doi:10.1124/pr.57.4.5. PMID16382099.
Perez-Reyes E, Castellano A, Kim HS, Bertrand P, Baggstrom E, Lacerda AE, Wei XY, Birnbaumer L (1992). "Cloning and expression of a cardiac/brain beta subunit of the L-type calcium channel". J. Biol. Chem. 267 (3): 1792–7. PMID1370480.
Barry EL, Viglione MP, Kim YI, Froehner SC (1995). "Expression and antibody inhibition of P-type calcium channels in human small-cell lung carcinoma cells". J. Neurosci. 15 (1 Pt 1): 274–83. PMID7823133.
Joutel A, Bousser MG, Biousse V, Labauge P, Chabriat H, Nibbio A, Maciazek J, Meyer B, Bach MA, Weissenbach J (1993). "A gene for familial hemiplegic migraine maps to chromosome 19". Nat. Genet. 5 (1): 40–5. doi:10.1038/ng0993-40. PMID8220421.
Margolis RL, Breschel TS, Li SH, Kidwai AS, Antonarakis SE, McInnis MG, Ross CA (1995). "Characterization of cDNA clones containing CCA trinucleotide repeats derived from human brain". Somat. Cell Mol. Genet. 21 (4): 279–84. doi:10.1007/BF02255782. PMID8525433.
Diriong S, Lory P, Williams ME, Ellis SB, Harpold MM, Taviaux S (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. PMID8825650.
Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR (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. PMID8898206.
Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC (1997). "Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel". Nat. Genet. 15 (1): 62–9. doi:10.1038/ng0197-62. PMID8988170.
De Waard M, Liu H, Walker D, Scott VE, Gurnett CA, Campbell KP (1997). "Direct binding of G-protein betagamma complex to voltage-dependent calcium channels". Nature. 385 (6615): 446–50. doi:10.1038/385446a0. PMID9009193.
Riess O, Schöls L, Bottger H, Nolte D, Vieira-Saecker AM, Schimming C, Kreuz F, Macek M, Krebsová A, Klockgether T, Zühlke C, Laccone FA (1997). "SCA6 is caused by moderate CAG expansion in the alpha1A-voltage-dependent calcium channel gene". Hum. Mol. Genet. 6 (8): 1289–93. doi:10.1093/hmg/6.8.1289. PMID9259275.
Jodice C, Mantuano E, Veneziano L, Trettel F, Sabbadini G, Calandriello L, Francia A, Spadaro M, Pierelli F, Salvi F, Ophoff RA, Frants RR, Frontali M (1997). "Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p". Hum. Mol. Genet. 6 (11): 1973–8. doi:10.1093/hmg/6.11.1973. PMID9302278.
Walker D, Bichet D, Campbell KP, De Waard M (1998). "A beta 4 isoform-specific interaction site in the carboxyl-terminal region of the voltage-dependent Ca2+ channel alpha 1A subunit". J. Biol. Chem. 273 (4): 2361–7. doi:10.1074/jbc.273.4.2361. PMID9442082.{{cite journal}}: CS1 maint: unflagged free DOI (link)
Walker D, Bichet D, Geib S, Mori E, Cornet V, Snutch TP, Mori Y, De Waard M (1999). "A new beta subtype-specific interaction in alpha1A subunit controls P/Q-type Ca2+ channel activation". J. Biol. Chem. 274 (18): 12383–90. doi:10.1074/jbc.274.18.12383. PMID10212211.{{cite journal}}: CS1 maint: unflagged free DOI (link)
