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The putative cache (Ca 2+ channel and chemotaxis receptor) domain containing 1 (CACHD1) protein has predicted structural similarities to members of the α2δ voltage-gated Ca 2+ 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 V 3 subunits, in particular Ca V 3.1. In expression studies, CACHD1 increased cell-surface localization of Ca V 3.1, and these proteins were in close proximity at the cell surface, consistent with the formation of CACHD1-Ca V 3.1 complexes. In functional electrophysiological studies, coexpression of human CACHD1 with Ca V 3.1, Ca V 3.2, and Ca V 3.3 caused a significant increase in peak current density and corresponding increases in maximal conductance. By contrast, α2δ-1 had no effect on peak current density or maximal conductance in Ca V 3.1, Ca V 3.2, or Ca V 3.3. A comparison of CACHD1-mediated increases in Ca V 3.1 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 V 3-mediated action potential firing frequency and neuronal excitability. These data suggest that CACHD1 is structurally an α2δ-like protein that functionally modulates Ca V 3 voltage-gated calcium channel activity. SIGNIFICANCE STATEMENT This is the first study to characterize the Ca 2+ 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 V 3, T-type) calcium channels, in particular to Ca V 3.1, a protein that regulates neuronal excitability and is a potential therapeutic target in conditions such as epilepsy and pain. CACHD1 is structurally an α2δ-like protein that functionally increases Ca V 3 calcium current. CACHD1 increases the presence of Ca V 3.1 at the cell surface, forms complexes with Ca V 3.1 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 V 3 activity.

CACHD1 is an α2δ-Like Protein That Modulates CaV3 Voltage-Gated Calcium Channel Activity

CACHD1 is an α2δ-Like Protein That Modulates Ca_V3 Voltage-Gated Calcium Channel Activity