CACNA1C and Associated Diseases

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Overview of CACNA1C

Calcium channels can be divided into ligand-gated calcium channels (LGCCs) and voltage-gated calcium channels (VGCCs). As a type of VGCCs, calcium voltage-gated channel subunit alpha1C (CACNA1C) was coded by the α1 subunit Cav1.2. The CACNA1C channel consists of 4 homologous domains (DI-DIV), each comprised of 6 transmembrane segments, cytoplasmic segments, and transmembrane linkers. CACNA1C is broadly expressed and best studied in the human heart, brain, smooth muscle, and endocrine tissue. In the central nervous system, CACNA1C shows the highest expression in the cerebral cortex, hippocampi, thalami, nucleus cerebellum, and suprachiasmatic.

CACNA1C protein topology. Fig.1 CACNA1C protein topology. (Boczek, 2015)

Function of CACNA1C

CACNA1C plays an important role in the development and function of the central nervous system. It influences neuronal firing by modulating calcium channel functions. Moreover, it modulates γ-aminobutyric acid transmitting interneuron function. Therefore, CACNA1C could affect brain regional activation and inter-regional connectivity. It has been reported to be involved in the regulation of cell-matrix adhesion, cell adhesion, collagen fibrous tissue, cell response to amino acid stimulation, and negative regulation of cell proliferation. The CACNA1C was also up-regulated in brain tumors, leukemia, breast cancer, and other tumors, suggesting its regulatory role in cancer progression. All these suggest that CACNA1C can be used as a prognostic biomarker of human cancer.

CACNA1C Genetic Variation

CACNA1C is located on the short arm of chromosome 12p13.3, spanning an approximately 6.45 Mb genomic region. Many single nucleotide polymorphisms (SNPs) in CACNA1C, concentrated within the large 328.5-kb intron 3, have been linked to psychiatric illness. It is well known that CACNA1C transcripts are subject to extensive alternative splicing, with thousands of splicing variants possible. CACNA1C is expressed in many tissues at different stages of human development. Transcription expression is species- and tissue-dependent and subject to developmental regulation and pathophysiological conditions. The majority of known splice variation, which predominates on the 3′ end of the gene, is not in proximity to genetic changes associated with mood disorders and schizophrenia. However, the diversity of CACNA1C splice variants is relevant to studying the function of this gene in psychiatric disorders and may have important implications for understanding the mechanisms of the disease. It also provides avenues to inquire about potential targets for drug development and selective modification of physiological functions.

Mental disorder significant findings projected on the genomic map of CACNA1C. Fig.2 Mental disorder significant findings projected on the genomic map of CACNA1C. (Bhat, 2012)

CACNA1Cin Disease

The effect of CACNA1C on cognitive function appears to be mediated by L-type voltage-gated calcium channel Cav1.2, which is expressed in the cardiovascular system and throughout the nervous system.

  • Pathogenic variants in CACNA1C are associated with various cardiac rhythm disorders, this gene has also been implicated in diverse neurological phenotypes. Polymorphisms in the CACNA1C gene have been associated with an increased risk of schizophrenia, bipolar disorder, major depressive disorder, and autism. Cav1.2 couples transient activation of inward calcium current to transcriptional regulation and plays an important role in dendrite development, memory formation, synaptic plasticity, neuronal survival, learning, and behavior.
  • As a voltage-dependent calcium ion transmembrane channel, CACNA1C plays a regulatory role in the occurrence and development of a variety of tumors

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References

  1. Boczek, N.J.; et al. Novel Timothy syndrome mutation leading to increase in CACNA1C window current. Heart Rhythm. 2015 Jan;12(1):211-9.
  2. Bhat, S.; et al. CACNA1C (Cav1. 2) in the pathophysiology of psychiatric disease. Progress in neurobiology. 2012, 99(1): 1-14.
For research use only. Not intended for any clinical use.