Ca_v1.2

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).[7]

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.[8] Cav1.2 is widely expressed in the smooth muscle, pancreatic cells, fibroblasts, and neurons.[9][10] 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.[8] The protein encoded by this gene binds to and is inhibited by dihydropyridine.[11] 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.[12] Cav1.2 also regulates levels of osteoprotegerin.[13]

Ca_V1.2 is inhibited by the action of STIM1.[14]

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.[15] These activation and inactivation mechanisms both involve Ca²⁺ binding to calmodulin (CaM) in the IQ domain in the C-terminal tail of these channels.[16] 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.[17] 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.[17]

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.

Mutation in the CACNA1C gene, the single-nucleotide polymorphism located in the third intron of the Cav1.2 gene,[18] are associated with a variant of Long QT syndrome called Timothy's syndrome[19] and more broadly with other CACNA1C-related disorders,[19] and also with Brugada syndrome.[20] Large-scale genetic analyses have shown the possibility that CACNA1C is associated with bipolar disorder[21] and subsequently also with schizophrenia.[22][23][24] 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.[25].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 ability_efficiency scores. Subjects with genotypes carrying the risk allele of rs1006737 (G/A and A/A) were found to have higher spatial ability_efficiency 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 memory_{processing 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).[26]

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

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|alt=Nicotine Activity on Chromaffin Cells edit]]

Nicotine Activity on Chromaffin Cells edit

1. The interactive pathway map can be edited at WikiPathways: "NicotineActivityonChromaffinCells_WP1603".

• Calcium channel
• Calcium channel associated transcriptional regulator

• GeneReviews/NIH/NCBI/UW entry on Brugada syndrome
• CACNA1C+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• GeneReviews/NIH/NCBI/UW entry on Timothy Syndrome

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