Cav1.2

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Calcium channel, voltage-dependent, L type, alpha 1C subunit
250px
PDB rendering based on 2be6.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CACNA1C ; CACH2; CACN2; CACNL1A1; CCHL1A1; CaV1.2; LQT8; TS
External IDs OMIM114205 MGI103013 HomoloGene55484 IUPHAR: 529 ChEMBL: 1940 GeneCards: CACNA1C Gene
Orthologs
Species Human Mouse
Entrez 775 12288
Ensembl ENSG00000151067 ENSMUSG00000051331
UniProt Q13936 Q01815
RefSeq (mRNA) NM_000719 NM_001159533
RefSeq (protein) NP_000710 NP_001153005
Location (UCSC) Chr 12:
1.97 – 2.7 Mb
Chr 6:
118.59 – 119.2 Mb
PubMed search [2] [3]

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 into the cell upon membrane polarization. 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.[3] Cav1.2 is widely expressed in the smooth muscle, pancreatic cells, fibroblasts, and neurons.[4][5] 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.[3] The protein encoded by this gene binds to and is inhibited by dihydropyridine.[6] 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.[7] Cav1.2 also regulates levels of osteoprotegerin.[8]

CaV1.2 is inhibited by the action of STIM1.[9]

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.[10] These activation and inactivation mechanisms both involve Ca2+ binding to calmodulin (CaM) in the IQ domain in the C-terminal tail of these channels.[11] 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.[12] 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.[12]

File:Ca1.2channelclutsering.png
Due to simplicity only two Calcium channels are shown to depict clustering. When depolarization occurs, calcium ions flow through the channel and some bind to Calmodulin. The Calcium/Calmodulin binding to the C-terminal pre-IQ domain of the Cav1.2 channel promotes interaction between channels that are beside each other.

Clinical significance

Mutation in the CACNA1C gene, the single-nucleotide polymorphism located in the third intron of the Cav1.2 gene,[13] are associated with a variant of Long QT syndrome called Timothy's syndrome[14] and also with Brugada syndrome.[15] A large-scale genetic analysis conducted in 2008 shows the possibility that CACNA1C is associated with bipolar disorder [16] and subsequently also with schizophrenia.[17][18] Also, CACNA1C A 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.[19]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective Wikipedia articles. [§ 1]

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Nicotine Activity on Chromaffin Cells edit
  1. The interactive pathway map can be edited at WikiPathways: Lua error in package.lua at line 80: module 'strict' not found.

See also

References

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  12. 12.0 12.1 [1], Graded Ca2+/calmodulin-dependent coupling of voltage-gated CaV1.2 channels
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Further reading

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External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.