Cav1.2 Explained

Calcium channel, voltage-dependent, L type, alpha 1C subunit (also known as Cav1.2) is a protein that in humans is encoded by the CACNA1C gene.[1] Cav1.2 is a subunit of L-type voltage-dependent calcium channel.[2]

Structure and function

This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions (Ca2+) into the cell upon membrane polarization (see membrane potential and calcium in biology).[3]

The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta and beta subunits in a 1:1:1 ratio. The S3-S4 linkers of Cav1.2 determine the gating phenotype and modulated gating kinetics of the channel.[4] Cav1.2 is widely expressed in the smooth muscle, pancreatic cells, fibroblasts, and neurons.[5] [6] However, it is particularly important and well known for its expression in the heart where it mediates L-type currents, which causes calcium-induced calcium release from the ER Stores via ryanodine receptors. It depolarizes at -30mV and helps define the shape of the action potential in cardiac and smooth muscle.[4] The protein encoded by this gene binds to and is inhibited by dihydropyridine.[7] In the arteries of the brain, high levels of calcium in mitochondria elevates activity of nuclear factor kappa B NF-κB and transcription of CACNA1c and functional Cav1.2 expression increases.[8] Cav1.2 also regulates levels of osteoprotegerin.[9]

CaV1.2 is inhibited by the action of STIM1.[10]

Regulation

The activity of CaV1.2 channels is tightly regulated by the Ca2+ signals they produce. An increase in intracellular Ca2+ concentration implicated in Cav1.2 facilitation, a form of positive feedback called Ca2+-dependent facilitation, that amplifies Ca2+ influx. In addition, increasing influx intracellular Ca2+ concentration has implicated to exert the opposite effect Ca2+ dependent inactivation.[11] These activation and inactivation mechanisms both involve Ca2+ binding to calmodulin (CaM) in the IQ domain in the C-terminal tail of these channels.[12] Cav1.2 channels are arranged in cluster of eight, on average, in the cell membrane. When calcium ions bind to calmodulin, which in turn binds to a Cav1.2 channel, it allows the Cav1.2 channels within a cluster to interact with each other.[13] This results in channels working cooperatively when they open at the same time to allow more calcium ions to enter and then close together to allow the cell to relax.[13]

Clinical significance

Mutation in the CACNA1C gene, the single-nucleotide polymorphism located in the third intron of the Cav1.2 gene,[14] are associated with a variant of Long QT syndrome called Timothy's syndrome and more broadly with other CACNA1C-related disorders,[15] and also with Brugada syndrome.[16] Large-scale genetic analyses have shown the possibility that CACNA1C is associated with bipolar disorder[17] and subsequently also with schizophrenia.[18] [19] [20] Also, a CACNA1C risk allele has been associated to a disruption in brain connectivity in patients with bipolar disorder, while not or only to a minor degree, in their unaffected relatives or healthy controls.[21] In a first study in Indian population, the Schizophrenia associated Genome-wide association study (GWAS) SNP was found not to be associated with the disease. Furthermore, the main effect of rs1006737 was found to be associated with spatial abilityefficiency scores. Subjects with genotypes carrying the risk allele of rs1006737 (G/A and A/A) were found to have higher spatial abilityefficiency scores as compared to those with the G/G genotype. While in healthy controls those with G/A and A/A genotypes were found to have higher spatial memoryprocessing speed scores than those with G/G genotypes, the former had lower scores than the latter in schizophrenia subjects. In the same study the genotypes with the risk allele of rs1006737 namely A/A was associated with a significantly lower Align rank transformed Abnormal and involuntary movement scale(AIMS) scores of Tardive dyskinesia(TD).[22]

See also

Further reading

External links

Notes and References

  1. Lacerda AE, Kim HS, Ruth P, Perez-Reyes E, Flockerzi V, Hofmann F, Birnbaumer L, Brown AM . Normalization of current kinetics by interaction between the alpha 1 and beta subunits of the skeletal muscle dihydropyridine-sensitive Ca2+ channel . Nature . 352 . 6335 . 527–30 . Aug 1991 . 1650913 . 10.1038/352527a0 . 1991Natur.352..527L . 4246540 .
  2. Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J . International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels . Pharmacological Reviews . 57 . 4 . 411–25 . Dec 2005 . 16382099 . 10.1124/pr.57.4.5 . 10386627 .
  3. Shaw RM, Colecraft HM . L-type calcium channel targeting and local signalling in cardiac myocytes . Cardiovascular Research . 98 . 2 . 177–86 . May 2013 . 23417040 . 10.1093/cvr/cvt021 . 3633156.
  4. Lipscombe D, Helton TD, Xu W . L-type calcium channels: the low down . Journal of Neurophysiology . 92 . 5 . 2633–41 . Nov 2004 . 10.1152/jn.00486.2004 . 15486420 . 52887174 .
  5. Christel C, Lee A . Ca2+-dependent modulation of voltage-gated Ca2+ channels . Biochimica et Biophysica Acta (BBA) - General Subjects . 1820 . 8 . 1243–52 . Aug 2012 . 22223119 . 10.1016/j.bbagen.2011.12.012 . 3345169 .
  6. Berger SM, Bartsch D . The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function . Cell and Tissue Research . 357 . 2 . 463–76 . Aug 2014 . 24996399 . 10.1007/s00441-014-1936-3 . 15914718 .
  7. Web site: Entrez Gene: voltage-dependent, L type, alpha 1C subunit .
  8. Narayanan D, Xi Q, Pfeffer LM, Jaggar JH . Mitochondria control functional CaV1.2 expression in smooth muscle cells of cerebral arteries . Circulation Research . 107 . 5 . 631–41 . Sep 2010 . 20616314 . 3050675 . 10.1161/CIRCRESAHA.110.224345 .
  9. Bergh JJ, Xu Y, Farach-Carson MC. Mary Cynthia Farach-Carson . Osteoprotegerin expression and secretion are regulated by calcium influx through the L-type voltage-sensitive calcium channel . Endocrinology . 145 . 1 . 426–36 . Jan 2004 . 14525906 . 10.1210/en.2003-0319 . free .
  10. Cahalan MD . Cell biology. How to STIMulate calcium channels . Science . 330 . 6000 . 43–4 . Oct 2010 . 20929798 . 10.1126/science.1196348 . 3133971.
  11. Isaev D, Solt K, Gurtovaya O, Reeves JP, Shirokov R . Modulation of the voltage sensor of L-type Ca2+ channels by intracellular Ca2+ . The Journal of General Physiology . 123 . 5 . 555–71 . May 2004 . 15111645 . 10.1085/jgp.200308876 . 2234499 .
  12. Kim EY, Rumpf CH, Van Petegem F, Arant RJ, Findeisen F, Cooley ES, Isacoff EY, Minor DL . Multiple C-terminal tail Ca(2+)/CaMs regulate Ca(V)1.2 function but do not mediate channel dimerization . The EMBO Journal . 29 . 23 . 3924–38 . Dec 2010 . 20953164 . 10.1038/emboj.2010.260 . 3020648 .
  13. 4360655 . 25714924 . 10.7554/eLife.05608 . 4 . Graded Ca²⁺/calmodulin-dependent coupling of voltage-gated CaV1.2 channels . eLife . Dixon RE, Moreno CM, Yuan C, Opitz-Araya X, Binder MD, Navedo MF, Santana LF. 2015 . free .
  14. Imbrici P, Camerino DC, Tricarico D . Major channels involved in neuropsychiatric disorders and therapeutic perspectives . Frontiers in Genetics . 4 . 76 . 2013-05-07 . 23675382 . 10.3389/fgene.2013.00076 . 3646240 . free .
  15. Book: Napolitano C, Timothy KW, Bloise R, Priori SG . CACNA1C-Related Disorders . 1993 . GeneReviews® . Seattle (WA) . University of Washington, Seattle . 20301577 . 2022-12-12 . Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A .
  16. Hedley PL, Jørgensen P, Schlamowitz S, Moolman-Smook J, Kanters JK, Corfield VA, Christiansen M . The genetic basis of Brugada syndrome: a mutation update . Human Mutation . 30 . 9 . 1256–66 . Sep 2009 . 19606473 . 10.1002/humu.21066 . 25207473 .
  17. Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, Fan J, Kirov G, Perlis RH, Green EK, Smoller JW, Grozeva D, Stone J, Nikolov I, Chambert K, Hamshere ML, Nimgaonkar VL, Moskvina V, Thase ME, Caesar S, Sachs GS, Franklin J, Gordon-Smith K, Ardlie KG, Gabriel SB, Fraser C, Blumenstiel B, Defelice M, Breen G, Gill M, Morris DW, Elkin A, Muir WJ, McGhee KA, Williamson R, MacIntyre DJ, MacLean AW, St CD, Robinson M, Van Beck M, Pereira AC, Kandaswamy R, McQuillin A, Collier DA, Bass NJ, Young AH, Lawrence J, Ferrier IN, Anjorin A, Farmer A, Curtis D, Scolnick EM, McGuffin P, Daly MJ, Corvin AP, Holmans PA, Blackwood DH, Gurling HM, Owen MJ, Purcell SM, Sklar P, Craddock N . 6 . Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder . Nature Genetics . 40 . 9 . 1056–8 . Sep 2008 . 18711365 . 2703780 . 10.1038/ng.209.
  18. Green EK, Grozeva D, Jones I, Jones L, Kirov G, Caesar S, Gordon-Smith K, Fraser C, Forty L, Russell E, Hamshere ML, Moskvina V, Nikolov I, Farmer A, McGuffin P, Holmans PA, Owen MJ, O'Donovan MC, Craddock N . The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia . Molecular Psychiatry . 15 . 10 . 1016–22 . Oct 2010 . 19621016 . 3011210 . 10.1038/mp.2009.49 .
  19. Curtis D, Vine AE, McQuillin A, Bass NJ, Pereira A, Kandaswamy R, Lawrence J, Anjorin A, Choudhury K, Datta SR, Puri V, Krasucki R, Pimm J, Thirumalai S, Quested D, Gurling HM . Case-case genome-wide association analysis shows markers differentially associated with schizophrenia and bipolar disorder and implicates calcium channel genes . Psychiatric Genetics . 21 . 1 . 1–4 . Feb 2011 . 21057379 . 3024533 . 10.1097/YPG.0b013e3283413382 .
  20. Schizophrenia Working Group of the Psychiatric Genomics Consortium . 2014-07-24 . Biological insights from 108 schizophrenia-associated genetic loci . Nature . 511 . 7510 . 421–427 . 10.1038/nature13595 . 1476-4687 . 4112379 . 25056061 . 2014Natur.511..421S.
  21. Radua J, Surguladze SA, Marshall N, Walshe M, Bramon E, Collier DA, Prata DP, Murray RM, McDonald C . The impact of CACNA1C allelic variation on effective connectivity during emotional processing in bipolar disorder . Molecular Psychiatry . 18 . 5 . 526–7 . May 2013 . 22614292 . 10.1038/mp.2012.61 . free .
  22. Punchaichira TJ, Kukshal P, Bhatia T, Deshpande SN. Effect of rs1108580 of DBH and rs1006737 of CACNA1C on Cognition and Tardive Dyskinesia in a North Indian Schizophrenia Cohort . Molecular Neurobiology . 2023 . 60 . 12 . 6826–6839 . 37493923. 10.1007/s12035-023-03496-4 . 260162784 .

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