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cacna1c

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Official Full Name
calcium channel, voltage-dependent, L type, alpha 1C subunit
Background
Ion channels are integral membrane proteins that help establish and control the small voltage gradient across the plasma membrane of living cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells because their main function is to regulate the flow of ions across this membrane. Whereas some ion channels permit the passage of ions based on charge, others conduct based on a ionic species, such as sodium or potassium. Furthermore, in some ion channels, the passage is governed by a gate which is controlled by chemical or electrical signals, temperature, or mechanical forces. There are a few main classifications of gated ion channels. There are voltage-gated ion channels, ligand-gated, other gating systems, and finally those that are classified differently, having more exotic characteristics. Specifically, Cav1.2 is a cardiac L-type calcium channel and is important for excitation and contraction of the heart. It may be associated with a variant of Long QT syndrome called Timothy’s syndrome and also with Brugada syndrome. Some references suggest it is related to bipolar disease as well.
Synonyms
CACNA1C; Cav1.2 Calcium Channel; calcium channel, voltage-dependent, L type, alpha 1C subunit; TS; CACH2; CACN2; CaV1.2; CCHL1A1; CACNL1A1; MGC120730; voltage-dependent L-type calcium channel subunit alpha-1C; DHPR, alpha-1 subunit; calcium channel, cardic dihydropyridine-sensitive, alpha-1 subunit; calcium channel, L type, alpha-1 polypeptide, isoform 1, cardiac muscle; voltage-gated L-type calcium channel Cav1.2 alpha 1 subunit, splice variant 10*; Voltage-gated calcium channel subunit alpha Cav1.2; OTTHUMP00000196730; OTTHUMP00000196731; OTTHUMP00000196732; OTTHUMP00000196733; OTTHUMP00000196734; OTTHUMP00000196735; OTTHUMP00000196736; OTTHUMP00000196737; OTTHUMP00000196738; OTTHUMP00000196739; OTTHUMP00000196740; OTTHUMP00000196741; OTTHUMP00000196742; OTTHUMP00000196743; OTTHUMP00000196744; OTTHUMP00000196745; OTTHUMP00000196746; OTTHUMP00000196747; OTTHUMP00000196748; OTTHUMP00000196749; OTTHUMP00000196750; OTTHUMP00000196751; OTTHUMP00000238277; OTTHUMP00000238278; OTTHUMP00000238279; isl; C-LTCC; ZfCav1.2; island beat; CACB

Recent Research Progress

The CACNA1C gene is located on chromosome 12p13.3 and encodes the alpha-1 subunit of the L-type voltage-dependent gated calcium channel. Calcium influx through these channels is combined with signaling pathways that stimulate the expression of genes necessary for neuronal survival and plasticity. The CACNA1C gene has been reported to be a candidate risk gene for a variety of neuropsychiatric disorders, including bipolar disorder (BD), major depressive disorder (MDD) and schizophrenia.

CACNA1C and MDD

MDD is a complex mental illness that is moderately heritable and has an estimated heritability of approximately 40%. Recently, genetic studies have found that the A allele of the single nucleotide polymorphism (SNPs) rs1006737 in the CACNA1C gene, which encodes for the alpha 1C subunit of the voltage-dependent, L-type calcium ion channel Cav1.2, to be overrepresented in patients with MDD. The current data provide further evidence for the effect of rs1006737 on left inferior frontal gyrus (IFG) and demonstrate that genetic variation in CACNA1C regulates neural responses in MDD patients. The observed functional changes in the prefrontal and cerebellar regions may represent a mechanism by which rs1006737 affects MDD susceptibility.

CACNA1C and BD

BD is a common complex mental disorder characterized by mania, hypomania and depression. The disease affects approximately 1% of the population and the genetic risk component is high with heritability estimates reaching 89%. CACNA1C is one of the most consistent BD genes. CACNA1C hypermethylation in whole blood of BD patients has been determined. Recent studies have shown that the regulation of risk alleles in intron 3 is accompanied by an upward shift in DNA methylation of intron 3 CpG Islands (CGI). In conclusion, CACNA1C DNA methylation may play a role in BD.

CACNA1C and Diabetic Cataract

Diabetic cataract is one of the major eye complications of diabetes. It has been reported that cataract occurs two to five times more frequently in patients with diabetes compared with those with no diabetes. The CACNA1C gene has been found to be associated with diabetic cataracts. Cheng Chang et al.used the genome-wide association studies (GWAS) method to determine that the CACNA1C gene is associated with diabetic cataract in the Scottish Diabetes Cohort. They also reported significant differences in blood calcium levels between diabetic cataract cases and controls, suggesting a potential role for calcium in the development of cataracts.

CACNA1C and Schizophrenia

Schizophrenia is a common and serious mental illness affecting about 1% of the world's population. Findings from family, adoption and twin studies indicated that the risk of schizophrenia has a strong genetic component and the heritability of schizophrenia has been estimated to be close to 80%. In recent years, many schizophrenia susceptibility areas have been identified through GWASs, including CACNA1C, major histocompatibility complex, TCF4 and ZNF804A. Among these risk loci, CACNA1C is one of the most promising candidate genes; one of the intron SNPs, rs1006737 showed the most significant association with schizophrenia among CACNA1C region in a European GWAS; in the latest and largest schizophrenia GWAS, although rs1006737 is not the highest risk SNP in the CACNA1C region, it is still significantly associated with schizophrenia.

In summary, CACNA1C is associated with many mental illnesses. Therefore, further study of its pathogenesis in mental illness will provide valuable and meaningful clues for disease treatment.

References:

  1. Xiao Ou, et al. CACNA1C rs1006737 genotype and bipolar disorder: Focus on intermediate phenotypes and cardiovascular comorbidity. Neuroscience and Biobehavioral Reviews,  2015, 55 : 198–210.
  2. Jessica A, et al. A CACNA1C Variant Associated with Reduced VoltageDependent Inactivation, Increased CaV1.2 Channel Window Current, and Arrhythmogenesis. Plos One, 2014: e106982.
  3. Backes H, et al. Genetic variation in CACNA1C affects neural processing in major depression. Journal of Psychiatric Research, 2014, 53: 38e46.
  4. Starnawska A, et al. CACNA1C hypermethylation is associated with bipolar disorder. Translational Psychiatry, 2016, 1: 7.
  5. Claudia Wolf, et al. CACNA1C genotype explains interindividual differences in amygdala volume among patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci, 2014, 264:93–102.
  6. Jun Li, et al. Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism. Plos One, 2015, 10(7): e0133247.
  7. Megumi Fukuyama, et al. Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes. Europace, 2014, 16: 1828–1837.
  8. Hongyan Jiang, et al. Evaluating the association between CACNA1C rs1006737 and schizophrenia risk: A meta-analysis. Asia-Pacific Psychiatry, 2015, 7: 260–267.
  9. ZD Kabir, et al. Cacna1c in the Prefrontal Cortex Regulates Depression-Related Behaviors via REDD1. Neuropsychopharmacology, 2017, 42: 2032–2042.
  10. Cheng Chang, et al. A Genome-Wide Association Study Provides New Evidence That CACNA1C Gene is Associated With Diabetic Cataract. Vis Sci, 2016, 57:2246–2250.
  11. Anni S, et al. The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons. March, 2016, 3(2): e0006.
  12. Boczek, et al. Identification and Functional Characterization of a Novel CACNA1C-Mediated Cardiac Disorder Characterized by Prolonged QT Intervals With Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death. Circ Arrhythm Electrophysiol, 2015, 8:1122-1132.
  13. Susanne Erk, et al. Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects. NeuroImage, 2014, 94: 147–154.