CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease

Abstract

One of the most consistent genetic findings to have emerged from bipolar disorder genome wide association studies (GWAS) is with CACNA1C, a gene that codes for the α1C subunit of the Cav1.2 voltage-dependent L-type calcium channel (LTCC). Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders, as well as changes in brain function and structure in control subjects who have no diagnosable psychiatric illness. These data are consistent with a continuum of shared neurobiological vulnerability between diverse—Diagnostic and Statistical Manual (DSM) defined—neuropsychiatric diseases. While involved in numerous cellular functions, Cav1.2 is most frequently implicated in coupling of cell membrane depolarization to transient increase of the membrane permeability for calcium, leading to activation and, potentially, changes in intracellular signaling pathway activity, gene transcription, and synaptic plasticity. Cav1.2 is involved in the proper function of numerous neurological circuits including those involving the hippocampus, amygdala, and mesolimbic reward system, which are strongly implicated in psychiatric disease pathophysiology. A number of behavioral effects of LTCC inhibitors have been described including antidepressant-like behavioral actions in rodent models. Clinical studies suggest possible treatment effects in a subset of patients with mood disorders. We review the genetic structure and variation of CACNA1C, discussing relevant human genetic and clinical findings, as well as the biological actions of Cav1.2 that are most relevant to psychiatric illness.

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…Indeed, largescale genome-wide association studies (GWASs) revealed a strong association between susceptibility for various psychiatric disorders, including bipolar disease, schizophrenia, and major depression, and single nucleotide polymorphisms (SNPs) in the CACNA1C gene. These are located within intronic regions (Bhat et al, 2012). SNP rs1006737, a common intronic risk haplotype, is one of the most consistent associations in psychiatric genetics (Bhat et al, 2012;Yoshimizu et al, 2015).…”

“…These are located within intronic regions (Bhat et al, 2012). SNP rs1006737, a common intronic risk haplotype, is one of the most consistent associations in psychiatric genetics (Bhat et al, 2012;Yoshimizu et al, 2015). It also has an impact on task-based human behaviors and human brain morphology, such as gray matter volume of specific regions (for references, see Yoshimizu et al, 2015).…”

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability

“…These voltage-dependent calcium channels have been described to be associated with epilepsy and several neuropsychiatric disorders such as autism and schizophrenia. [1][2][3] Typically, these channels are composed of four subunits: an alpha1, alpha2-delta, beta and gamma subunit, each encoded by several genes. The a 1 subunit is the primary subunit necessary for channel functioning and in total 10 genes are known to encode this subunit.…”

Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome

“…The L-type calcium channel, Ca v 1.2, plays a central role in regulating an activity-dependent signaling network that is essential for neuronal function [1][2][3][4][5][6]. A particularly salient example of a perturbation in Ca v 1.2 function is Timothy syndrome (TS), a rare genetic disorder caused by dominant mutations in the gene CACNA1C, which encodes the α subunit of the voltage-gated calcium channel Ca v 1.2.…”