The α₂δ-like Protein Cachd1 Increases N-type Calcium Currents and Cell Surface Expression and Competes with α₂δ-1

Voltage-gated calcium channel auxiliary α2δ subunits are important for channel trafficking and function. Here, we compare the effects of α2δ-1 and an α2δ-like protein called Cachd1 on neuronal N-type (Ca_V2.2) channels, which are important in neurotransmission. Previous structural studies show the α2δ-1 VWA domain interacting with the first loop in Ca_V1.1 domain-I via its metal ion-dependent adhesion site (MIDAS) motif and additional Cache domain interactions. Cachd1 has a disrupted MIDAS motif. However, Cachd1 increases Ca_V2.2 currents substantially (although less than α2δ-1) and increases Ca_V2.2 cell surface expression by reducing endocytosis. Although the effects of α2δ-1 are abolished by mutation of Asp122 in Ca_V2.2 domain-I, which mediates interaction with its VWA domain, the Cachd1 responses are unaffected. Furthermore, Cachd1 co-immunoprecipitates with Ca_V2.2 and inhibits co-immunoprecipitation of α2δ-1 by Ca_V2.2. Cachd1 also competes with α2δ-1 for effects on trafficking. Thus, Cachd1 influences both Ca_V2.2 trafficking and function and can inhibit responses to α2δ-1.