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Review
. 2022 Dec 1:220:109262.
doi: 10.1016/j.neuropharm.2022.109262. Epub 2022 Sep 22.

CACNA1C (CaV1.2) and other L-type calcium channels in the pathophysiology and treatment of psychiatric disorders: Advances from functional genomics and pharmacoepidemiology

Paul J Harrison  1 , Syed M Husain  2 , Hami Lee  2 , Alejandro De Los Angeles  2 , Lucy Colbourne  3 , Arne Mould  3 , Nicola A L Hall  2 , Wilfried Haerty  4 , Elizabeth M Tunbridge  3
Affiliations
Review

CACNA1C (CaV1.2) and other L-type calcium channels in the pathophysiology and treatment of psychiatric disorders: Advances from functional genomics and pharmacoepidemiology

Paul J Harrison et al. Neuropharmacology. .

Abstract

A role for voltage-gated calcium channels (VGCCs) in psychiatric disorders has long been postulated as part of a broader involvement of intracellular calcium signalling. However, the data were inconclusive and hard to interpret. We review three areas of research that have markedly advanced the field. First, there is now robust genomic evidence that common variants in VGCC subunit genes, notably CACNA1C which encodes the L-type calcium channel (LTCC) CaV1.2 subunit, are trans-diagnostically associated with psychiatric disorders including schizophrenia and bipolar disorder. Rare variants in these genes also contribute to the risk. Second, pharmacoepidemiological evidence supports the possibility that calcium channel blockers, which target LTCCs, might have beneficial effects on the onset or course of these disorders. This is especially true for calcium channel blockers that are brain penetrant. Third, long-range sequencing is revealing the repertoire of full-length LTCC transcript isoforms. Many novel and abundant CACNA1C isoforms have been identified in human and mouse brain, including some which are enriched compared to heart or aorta, and predicted to encode channels with differing functional and pharmacological properties. These isoforms may contribute to the molecular mechanisms of genetic association to psychiatric disorders. They may also enable development of therapeutic agents that can preferentially target brain LTCC isoforms and be of potential value for psychiatric indications.

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Figures

Fig. 1
Fig. 1. Brain-penetrant calcium channel blockers and risk of psychiatric disorders.
The incidence of a first recorded psychiatric diagnosis during a two-year period is lower in patients taking a brain-penetrant CCB than those taking amlodipine, a CCB with low brain permeability (n = 44,732 in each cohort). Cohorts were propensity score matched at baseline for age, sex, race, blood pressure, body mass index, and for a range of medical diagnoses and medications. Risk ratios are shown with 95% confidence intervals. Similar results were seen when brain-penetrant CCBs were compared with verapamil and diltiazem. Data taken from Colbourne and Harrison (2022).
See this image and copyright information in PMC

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