CACHD1 is an {alpha}2{delta}-Like Protein That Modulates CaV3 Voltage-Gated Calcium Channel Activity

The putative cache (Ca²⁺ channel and chemotaxis receptor) domain containing 1 (CACHD1) protein has predicted structural similarities to members of the α2 voltage-gated Ca²⁺ channel 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 Ca_V3 subunits, in particular Ca_V3.1. In expression studies, CACHD1 increased cell-surface localization of Ca_V3.1, and these proteins were in close proximity at the cell surface, consistent with the formation of CACHD1-Ca_V3.1 complexes. In functional electrophysiological studies, coexpression of human CACHD1 with Ca_V3.1, Ca_V3.2, and Ca_V3.3 caused a significant increase in peak current density and corresponding increases in maximal conductance. By contrast, α2-1 had no effect on peak current density or maximal conductance in Ca_V3.1, Ca_V3.2, or Ca_V3.3. A comparison of CACHD1-mediated increases in Ca_V3.1 current density and gating currents revealed an increase in channel open probability. In hippocampal neurons from male and female embryonic day 19 rats, CACHD1 overexpression increased Ca_V3-mediated action potential firing frequency and neuronal excitability. These data suggest that CACHD1 is structurally an α2-like protein that functionally modulates Ca_V3 voltage-gated calcium channel activity.

SIGNIFICANCE STATEMENT This is the first study to characterize the Ca²⁺ channel and chemotaxis receptor domain containing 1 (CACHD1) protein. CACHD1 is widely expressed in the CNS, in particular in the thalamus, hippocampus, and cerebellum. CACHD1 distribution is similar to that of low voltage-activated (Ca_V3, T-type) calcium channels, in particular to Ca_V3.1, a protein that regulates neuronal excitability and is a potential therapeutic target in conditions such as epilepsy and pain. CACHD1 is structurally an α2-like protein that functionally increases Ca_V3 calcium current. CACHD1 increases the presence of Ca_V3.1 at the cell surface, forms complexes with Ca_V3.1 at the cell surface, and causes an increase in channel open probability. In hippocampal neurons, CACHD1 causes increases in neuronal firing. Thus, CACHD1 represents a novel protein that modulates Ca_V3 activity.

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