CACHD1 is an α2δ-Like Protein That Modulates Ca3 Voltage-Gated Calcium Channel Activity.

The putative cache (Ca channel and chemotaxis receptor) domain containing 1 (CACHD1) protein has predicted structural similarities to members of the α2δ voltage-gated Ca 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 Ca3 subunits, in particular Ca3.1. In expression studies, CACHD1 increased cell-surface localization of Ca3.1, and these proteins were in close proximity at the cell surface, consistent with the formation of CACHD1-Ca3.1 complexes. In functional electrophysiological studies, coexpression of human CACHD1 with Ca3.1, Ca3.2, and Ca3.3 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 Ca3.1, Ca3.2, or Ca3.3. A comparison of CACHD1-mediated increases in Ca3.1 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 Ca3-mediated action potential firing frequency and neuronal excitability. These data suggest that CACHD1 is structurally an α2δ-like protein that functionally modulates Ca3 voltage-gated calcium channel activity. This is the first study to characterize the Ca 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 (Ca3, T-type) calcium channels, in particular to Ca3.1, 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 Ca3 calcium current. CACHD1 increases the presence of Ca3.1 at the cell surface, forms complexes with Ca3.1 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 Ca3 activity.