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

Harrison, Paul J., Husain, Syed M., Lee, Hami, Los Angeles, Alejandro De, Colbourne, Lucy, Mould, Arne, Hall, Nicola A. L., Haerty, Wilfried ORCID: https://orcid.org/0000-0003-0111-191X and Tunbridge, Elizabeth M. (2022) CACNA1C (CaV1.2) and other L-type calcium channels in the pathophysiology and treatment of psychiatric disorders: Advances from functional genomics and pharmacoepidemiology. Neuropharmacology, 220. ISSN 0028-3908

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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.

Item Type: Article
Additional Information: Funding Information: Supported by the National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre, and an unrestricted grant from J&J Innovations to EMT and PJH. SH is part funded by a Marriott Scholarship from Wolfson College, Oxford. LC is a Wellcome Trust Clinical Doctoral Fellow. WH is supported by the Biotechnology and Biological Sciences Research Council (BBSRC). The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or the Department of Health and Social Care.
Uncontrolled Keywords: pharmacology,cellular and molecular neuroscience ,/dk/atira/pure/subjectarea/asjc/3000/3004
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 20 Oct 2022 10:30
Last Modified: 26 Oct 2022 09:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/89238
DOI: 10.1016/j.neuropharm.2022.109262

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