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CACNA1C  -  calcium channel, voltage-dependent, L type...

Homo sapiens

Synonyms: CACH2, CACN2, CACNL1A1, CCHL1A1, CaV1.2, ...
 
 
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Disease relevance of CACNA1C

  • CACNA1C polymorphisms are associated with the efficacy of calcium channel blockers in the treatment of hypertension [1].
  • RESULTS: The most potent of the inhibitors synthesized, N,O-didansyl-L-tyrosine (DDT), binds to Lactobacillus casei TS (LcTS) with 35-fold higher affinity and to Escherichia coli TS (EcTS) with 24-fold higher affinity than to human TS (hTS) [2].
  • Steady state kinetic studies have indicated the Escherichia coli thymidylate synthase (ecTS) is intrinsically more resistant to several TS-directed inhibitors as compared with the human enzyme, suggesting that ecTS is suitable for use as a drug-resistant marker [3].
  • In subacute sclerosing panencephalitis, we found an elevated level of TS and a decreased level of TH cells in both CSF and blood [4].
  • Of 90 females over the age of 18 presenting with TS, or with motor or vocal tics alone, nine had severe agoraphobia with panic attacks [5].
 

Psychiatry related information on CACNA1C

 

High impact information on CACNA1C

  • We show here that CD8+CD28(-) alloantigen-specific T suppressor (TS) cells induce the up-regulation of ILT3 and ILT4 on monocytes and dendritic cells, rendering these antigen-presenting cells (APCs) tolerogenic [6].
  • Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices [7].
  • These data indicate that gain-of-function mutations of CaV1.2 exons 8 and 8A cause distinct forms of TS [8].
  • We identified de novo missense mutations in exon 8 of CaV1.2 in both individuals [8].
  • A human Ca++ channel gene, CACNL1A1, and three human K+ channel genes--KCNA5, KCNA6, and KCNA1--map close to D12S99, but the Ca++ channel gene is unlikely to be the site of the defect, because crossovers have been observed to occur between the disease gene and a CA-repeat marker located close to this gene [9].
 

Chemical compound and disease context of CACNA1C

 

Biological context of CACNA1C

 

Anatomical context of CACNA1C

 

Associations of CACNA1C with chemical compounds

  • A human clone corresponding to the gene encoding the alpha 1 subunit of the cardiac dihydropyridine-sensitive calcium channel (CCHL1A1) has been isolated and partially sequenced [14].
  • Mutations introduced into the DHFR coding region by analogy with pyrimethamine-resistant malaria confer drug resistance to Toxoplasma, providing useful information on the structure of fused DHFR-TS enzymes and a powerful selectable marker for molecular genetic studies [21].
  • Thymidylate synthase (TS; 5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45) is essential for the de novo synthesis of thymidylate, a precursor of DNA [18].
  • Phosphorylation of serine 1928 in the distal C-terminal domain of cardiac CaV1.2 channels during beta1-adrenergic regulation [22].
  • A HYG targeting vector was utilized to replace the single dihydrofolate reductase-thymidylate synthase (DHFR-TS) gene remaining in a line heterozygous for a NEO replacement at the dhfr-ts locus (+/neo), with a targeting efficiency comparable to that seen with wild-type recipients [23].
 

Other interactions of CACNA1C

  • Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Ca(v beta2b)), CACNA2D1 (Ca(v alpha2delta1)), and CACNA1C tagged with enhanced yellow fluorescent protein (Ca(v)1.2) [13].
  • RT-PCR revealed NaV1.5, CaV1.2, and HCN-2 expression but we could not detect Kir2 [24].
  • Double labelling with an antibody against synapsin 1a showed that CaV1.3 subunits, but not CaV1.2 subunits, were always located at synaptic sites [25].
 

Analytical, diagnostic and therapeutic context of CACNA1C

  • Gel retardation assays confirmed a specific interaction between TS protein and its corresponding mRNA but not with unrelated mRNAs, including human placenta, human beta-actin, and yeast tRNA [18].
  • While the TS levels were uniformly higher when measured by ELISA, there was close proportional agreement between both assays (r2 = 0.84) [11].
  • Thymidylate synthase (TS, EC 2.1.1.45) is an important target enzyme for the fluoropyrimidines used in cancer chemotherapy [26].
  • TS was quantitated by Western immunoblot using monoclonal antibody TS106 [26].
  • Using the monoclonal antibody TS 106, we have developed an ultrasensitive enzyme-linked immunoassay (ELISA) for the detection and quantitation of TS [11].

References

  1. CACNA1C polymorphisms are associated with the efficacy of calcium channel blockers in the treatment of hypertension. Bremer, T., Man, A., Kask, K., Diamond, C. Pharmacogenomics (2006) [Pubmed]
  2. Predicting and harnessing protein flexibility in the design of species-specific inhibitors of thymidylate synthase. Fritz, T.A., Tondi, D., Finer-Moore, J.S., Costi, M.P., Stroud, R.M. Chem. Biol. (2001) [Pubmed]
  3. Retroviral expression of Escherichia coli thymidylate synthase cDNA confers high-level antifolate resistance to hematopoietic cells. Shaw, D., Berger, F.G., Spencer, H.T. Hum. Gene Ther. (2001) [Pubmed]
  4. Subacute sclerosing panencephalitis and progressive multiple sclerosis: T cell subsets in blood and CSF. Członkowska, A., Korlak, J., Iwińska, B. Neurology (1986) [Pubmed]
  5. Hereditary agoraphobia and obsessive-compulsive behaviour in relatives of patients with Gilles de la Tourette's syndrome. Comings, D.E., Comings, B.G. The British journal of psychiatry : the journal of mental science. (1987) [Pubmed]
  6. Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4. Chang, C.C., Ciubotariu, R., Manavalan, J.S., Yuan, J., Colovai, A.I., Piazza, F., Lederman, S., Colonna, M., Cortesini, R., Dalla-Favera, R., Suciu-Foca, N. Nat. Immunol. (2002) [Pubmed]
  7. Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices. Erxleben, C., Liao, Y., Gentile, S., Chin, D., Gomez-Alegria, C., Mori, Y., Birnbaumer, L., Armstrong, D.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Splawski, I., Timothy, K.W., Decher, N., Kumar, P., Sachse, F.B., Beggs, A.H., Sanguinetti, M.C., Keating, M.T. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  9. A gene for episodic ataxia/myokymia maps to chromosome 12p13. Litt, M., Kramer, P., Browne, D., Gancher, S., Brunt, E.R., Root, D., Phromchotikul, T., Dubay, C.J., Nutt, J. Am. J. Hum. Genet. (1994) [Pubmed]
  10. Phthalein derivatives as a new tool for selectivity in thymidylate synthase inhibition. Costi, P.M., Rinaldi, M., Tondi, D., Pecorari, P., Barlocco, D., Ghelli, S., Stroud, R.M., Santi, D.V., Stout, T.J., Musiu, C., Marangiu, E.M., Pani, A., Congiu, D., Loi, G.A., La Colla, P. J. Med. Chem. (1999) [Pubmed]
  11. Quantitation of thymidylate synthase in human tumors using an ultrasensitive enzyme-linked immunoassay. Johnston, P.G., Drake, J.C., Steinberg, S.M., Allegra, C.J. Biochem. Pharmacol. (1993) [Pubmed]
  12. The effects of indomethacin administration during pregnancy on women's and newborns' T-suppressor lymphocyte activity and on HLA class II expression by newborns' leukocytes. Durandy, A., Brami, C., Griscelli, C. American journal of reproductive immunology and microbiology : AJRIM. (1985) [Pubmed]
  13. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Antzelevitch, C., Pollevick, G.D., Cordeiro, J.M., Casis, O., Sanguinetti, M.C., Aizawa, Y., Guerchicoff, A., Pfeiffer, R., Oliva, A., Wollnik, B., Gelber, P., Bonaros, E.P., Burashnikov, E., Wu, Y., Sargent, J.D., Schickel, S., Oberheiden, R., Bhatia, A., Hsu, L.F., Haïssaguerre, M., Schimpf, R., Borggrefe, M., Wolpert, C. Circulation (2007) [Pubmed]
  14. Assignment of the human gene for the alpha 1 subunit of the cardiac DHP-sensitive Ca2+ channel (CCHL1A1) to chromosome 12p12-pter. Powers, P.A., Gregg, R.G., Lalley, P.A., Liao, M., Hogan, K. Genomics (1991) [Pubmed]
  15. Genomic structure of human L-type Ca2+ channel. Soldatov, N.M. Genomics (1994) [Pubmed]
  16. The structures of the human calcium channel alpha 1 subunit (CACNL1A2) and beta subunit (CACNLB3) genes. Yamada, Y., Masuda, K., Li, Q., Ihara, Y., Kubota, A., Miura, T., Nakamura, K., Fujii, Y., Seino, S., Seino, Y. Genomics (1995) [Pubmed]
  17. Mapping of a human brain voltage-gated calcium channel to human chromosome 12p13-pter. Sun, W., McPherson, J.D., Hoang, D.Q., Wasmuth, J.J., Evans, G.A., Montal, M. Genomics (1992) [Pubmed]
  18. Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase. Chu, E., Koeller, D.M., Casey, J.L., Drake, J.C., Chabner, B.A., Elwood, P.C., Zinn, S., Allegra, C.J. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  19. Sequestration of RNA in Alzheimer's disease neurofibrillary tangles and senile plaques. Ginsberg, S.D., Crino, P.B., Lee, V.M., Eberwine, J.H., Trojanowski, J.Q. Ann. Neurol. (1997) [Pubmed]
  20. Role of prostaglandin E2 in the induction of nonspecific T lymphocyte suppressor activity. Fischer, A., Durandy, A., Griscelli, C. J. Immunol. (1981) [Pubmed]
  21. Stable molecular transformation of Toxoplasma gondii: a selectable dihydrofolate reductase-thymidylate synthase marker based on drug-resistance mutations in malaria. Donald, R.G., Roos, D.S. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  22. Phosphorylation of serine 1928 in the distal C-terminal domain of cardiac CaV1.2 channels during beta1-adrenergic regulation. Hulme, J.T., Westenbroek, R.E., Scheuer, T., Catterall, W.A. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  23. Double targeted gene replacement for creating null mutants. Cruz, A., Coburn, C.M., Beverley, S.M. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  24. Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes. Satin, J., Kehat, I., Caspi, O., Huber, I., Arbel, G., Itzhaki, I., Magyar, J., Schroder, E.A., Perlman, I., Gepstein, L. J. Physiol. (Lond.) (2004) [Pubmed]
  25. Subcellular distribution of L-type Ca2+ channels responsible for plateau potentials in motoneurons from the lumbar spinal cord of the turtle. Simon, M., Perrier, J.F., Hounsgaard, J. Eur. J. Neurosci. (2003) [Pubmed]
  26. 5-fluorouracil-mediated thymidylate synthase induction in malignant and nonmalignant human cells. Parr, A.L., Drake, J.C., Gress, R.E., Schwartz, G., Steinberg, S.M., Allegra, C.J. Biochem. Pharmacol. (1998) [Pubmed]
 
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