Genetic Associations between Voltage-Gated Calcium Channels and Psychiatric Disorders

Abstract

Psychiatric disorders are mental, behavioral or emotional disorders. These conditions are prevalent, one in four adults suffer from any type of psychiatric disorders world-wide. It has always been observed that psychiatric disorders have a genetic component, however, new methods to sequence full genomes of large cohorts have identified with high precision genetic risk loci for these conditions. Psychiatric disorders include, but are not limited to, bipolar disorder, schizophrenia, autism spectrum disorder, anxiety disorders, major depressive disorder, and attention-deficit and hyperactivity disorder. Several risk loci for psychiatric disorders fall within genes that encode for voltage-gated calcium channels (CaVs). Calcium entering through CaVs is crucial for multiple neuronal processes. In this review, we will summarize recent findings that link CaVs and their auxiliary subunits to psychiatric disorders. First, we will provide a general overview of CaVs structure, classification, function, expression and pharmacology. Next, we will summarize tools to study risk loci associated with psychiatric disorders. We will examine functional studies of risk variations in CaV genes when available. Finally, we will review pharmacological evidence of the use of CaV modulators to treat psychiatric disorders. Our review will be of interest for those studying pathophysiological aspects of CaVs.

Zebrafish Larvae Carrying a Splice Variant Mutation in cacna1d: A New Model for Schizophrenia-Like Behaviours?

“…CACNA1D mutations have been implicated earlier in SCZ [8,13,21]. In behavioural pharmacology in rodents, the most common approach is to mimic psychotic-like positive symptoms by administering drugs that target N-methyl-D-aspartate (NMDA) (antagonism) or dopaminergic (agonism) receptors.…”

“…For example, there is evidence that rs100637 (a SCZ-associated SNP, located in intron 3 of the CACNA1C gene) is associated with major depressive disorder (MDD), SCZ and attention deficit hyperactivity disorder, leads to changes in CACNA1C expression in both human carriers [5,6] and induced human neurons [7]. In humans, broader phenotypes are present such as deficits in prepulse inhibition (PPI), latent inhibition and sleep disturbance in some SNP carriers, mimicking a broad spectrum of neuropsychiatric disorders [2,8].…”

“…In one study, two single nucleotide variants in CACNA1D were found in separate cohorts of bipolar patients [22]. Although a study in the Han Chinese population did not find an association of CACNA1D with SCZ [23], other subsequent studies did identify such an association [8,21]. Furthermore, wholeexome sequencing revealed variants in the CACNA1D coding region to be linked to ASD, depression, anxiety, fear and seizures [17,18].…”

Centipede Venom Peptides Acting on Ion Channels

“…Tuned calcium entry through Cavs is a key requirement for many cellular functions, such as the plateau of the cardiac action potential, contraction of muscle cells, generation of pacemaker potentials, release of hormones and neurotransmitters, sensory functions, and gene expression [78][79][80]. There are ten members of the Cav family in mammals-high-voltage-activated channels Cav1.1-1.4 and Cav2.1-2.3 and low-voltage-activated channels Cav3.1-3.3 [78].…”

“…ω-SLPTX5- Cav channels are closely related to several diseases. Mutations in the Cav gene cause hypokalemic periodic paralysis, migraine headache, psychiatric disorder, cardiac arrhythmia, autism, and developmental abnormalities [79,[84][85][86]. To date, two centipede peptides, ω-SLPTX 5 -Ssm1a and ω-SLPTX 13 -Ssm2a, have been identified as Cav channel modulators.…”