The α 2 δ-like Protein Cachd1 Increases N-type Calcium Currents and Cell Surface Expression and Competes with α 2 δ-1

• Published in: Cell reports (Cambridge) Vol. 25; no. 6; p. 1610
• Main Authors: Dahimene, Shehrazade, Page, Karen M, Kadurin, Ivan, Ferron, Laurent, Ho, Dominique Y, Powell, Gareth T, Pratt, Wendy S, Wilson, Stephen W, Dolphin, Annette C
• Format: Journal Article
• Language: English
• Published: United States 06.11.2018
• Subjects: Animals; Calcium Channels - genetics; Calcium Channels - metabolism; Calcium Channels, N-Type - genetics; Calcium Channels, N-Type - metabolism; Cell Membrane - metabolism; Hippocampus - metabolism; Ion Channel Gating; Male; Membrane Proteins - metabolism; Mutation - genetics; Neurites - metabolism; Protein Binding; Rats, Sprague-Dawley; interaction site; voltage-gated calcium channel; cache domain; Cachd1; cell surface expression
• ISSN: 2211-1247

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