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

This is the authors' abstract. We don't add key points for this paper.

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 V 2.2) channels, which are important in neurotransmission. Previous structural studies show the α2δ-1 VWA domain interacting with the first loop in Ca V 1.1 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 V 2.2 currents substantially (although less than α2δ-1) and increases Ca V 2.2 cell surface expression by reducing endocytosis. Although the effects of α2δ-1 are abolished by mutation of Asp122 in Ca V 2.2 domain-I, which mediates interaction with its VWA domain, the Cachd1 responses are unaffected. Furthermore, Cachd1 co-immunoprecipitates with Ca V 2.2 and inhibits co-immunoprecipitation of α2δ-1 by Ca V 2.2. Cachd1 also competes with α2δ-1 for effects on trafficking. Thus, Cachd1 influences both Ca V 2.2 trafficking and function and can inhibit responses to α2δ-1.