CACHD1 is an α2δ-like protein that modulates CaV3 voltage-gated calcium channel activity

Cottrell, G. S. ORCID: https://orcid.org/0000-0001-9098-7627, Soubrane, C. H., Hounshell, J. A., Lin, H., Owenson, V., Rigby, M., Cox, P. J., Barker, B. S., Ottolini, M., Ince, S., Bauer, C. C., Perez-Reyes, E., Patel, M. K., Stevens, E. B. and Stephens, G. J. ORCID: https://orcid.org/0000-0002-8966-4238 (2018) CACHD1 is an α2δ-like protein that modulates CaV3 voltage-gated calcium channel activity. The Journal of Neuroscience, 38 (4). pp. 9186-9201. ISSN 1529-2401 doi: 10.1523/JNEUROSCI.3572-15.2018

Abstract/Summary

The putative cache (Ca2+ channel and chemotaxis receptor) domain containing 1 (CACHD1) protein has predicted structural similarities to members of the alpha2delta voltage-gated Ca2+ channel (VGCC) auxiliary subunit family. CACHD1 mRNA and protein were highly expressed in the male mammalian CNS, in particular in the thalamus, hippocampus and cerebellum, with a broadly similar tissue distribution to CaV3 subunits, in particular, CaV3.1. In expression studies, CACHD1 increased cell-surface localization of CaV3.1 and these proteins were in close proximity at the cell surface consistent with the formation of CACHD1-CaV3.1 complexes. In functional electrophysiological studies, co-expression of human CACHD1 with CaV3.1, CaV3.2 and CaV3.3 caused a significant increase in peak current density and corresponding increases in maximal conductance. By contrast, alpha2delta-1 had no effect on peak current density or maximal conductance in either CaV3.1, CaV3.2 or CaV3.3. Comparison of CACHD1-mediated increases in CaV3.1 current density and gating currents revealed an increase in channel open probability. In hippocampal neurons from male and female E19 rats, CACHD1 overexpression increased CaV3-mediated action potential (AP) firing frequency and neuronal excitability. These data suggest that CACHD1 is structurally an alpha2delta-like protein that functionally modulates CaV3 voltage-gated calcium channel activity.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/79082
Identification Number/DOI	10.1523/JNEUROSCI.3572-15.2018
Refereed	Yes
Divisions	Interdisciplinary Research Centres (IDRCs) > Centre for Integrative Neuroscience and Neurodynamics (CINN) Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Publisher	The Society for Neuroscience
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