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

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• The Ca2+ channel and chemotaxis receptor domain containing 1 (CACHD1) protein's function is largely unknown.
• CACHD1 shares structural similarities with alpha2delta (α2δ) voltage-gated calcium channel auxiliary subunits.
• CACHD1 is notably expressed in the mammalian central nervous system (CNS), particularly in the thalamus, hippocampus, and cerebellum.

Purpose of the Study:

• To characterize the novel CACHD1 protein.
• To investigate the structural and functional relationship between CACHD1 and voltage-gated calcium channels.
• To determine the effect of CACHD1 on neuronal excitability.

Main Methods:

• Bioinformatic analysis for structural prediction.
• Quantitative PCR and Western blotting for tissue expression analysis.
• Cell-surface expression studies and co-immunoprecipitation.
• Electrophysiological recordings (whole-cell patch-clamp) in cell lines and primary neurons.

Main Results:

• CACHD1 exhibits broad expression in the CNS, mirroring the distribution of CaV3 calcium channel subunits.
• CACHD1 increases the cell-surface localization and forms complexes with CaV3.1 channels.
• Co-expression of CACHD1 with CaV3.1, CaV3.2, and CaV3.3 significantly enhances calcium channel current density and open probability.
• CACHD1 overexpression increases neuronal firing frequency and excitability in hippocampal neurons.

Conclusions:

• CACHD1 is a novel α2δ-like protein that positively modulates the activity of CaV3 (T-type) calcium channels.
• CACHD1 enhances CaV3 channel function by increasing cell-surface expression and open probability.
• CACHD1 represents a potential regulator of neuronal excitability with implications for neurological conditions like epilepsy and pain.