CACHD1 is an α2δ-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 alpha 2 delta 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(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, alpha 2 delta-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 alpha 2 delta-like protein that functionally modulates Ca(V)3 voltage-gated calcium channel activity.