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

• DOI: 10.1016/j.celrep.2018.10.033
• Publication Date: 2018-11-06T16:54:17Z
• Authors: Shehrazade Dahimene; Karen M. Page; Ivan Kadurin; Laurent Ferron; Dominique Y. Ho; Gareth T. Powell; Wendy S. Pratt; Stephen W. Wilson; Annette C. Dolphin
• Keywords: Male; 0301 basic medicine; QH301-705.5; Cell Membrane; Cachd1; Membrane Proteins; Hippocampus; Article; Rats, Sprague-Dawley; 03 medical and health sciences; interaction site; Calcium Channels, N-Type; Mutation; Neurites; Animals; cache domain; cell surface expression; Calcium Channels; Biology (General); voltage-gated calcium channel; Ion Channel Gating; Protein Binding

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 (CaV2.2) channels, which are important in neurotransmission. Previous structural studies show the α2δ-1 VWA domain interacting with the first loop in CaV1.1 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 CaV2.2 currents substantially (although less than α2δ-1) and increases CaV2.2 cell surface expression by reducing endocytosis. Although the effects of α2δ-1 are abolished by mutation of Asp122 in CaV2.2 domain-I, which mediates interaction with its VWA domain, the Cachd1 responses are unaffected. Furthermore, Cachd1 co-immunoprecipitates with CaV2.2 and inhibits co-immunoprecipitation of α2δ-1 by CaV2.2. Cachd1 also competes with α2δ-1 for effects on trafficking. Thus, Cachd1 influences both CaV2.2 trafficking and function and can inhibit responses to α2δ-1.