The α2δ-like Protein Cachd1 Increases N-type Calcium Currents and Cell Surface Expression and Competes with α2δ-1
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
DOI:
10.1016/j.celrep.2018.10.033
Publication Date:
2018-11-06T16:54:17Z
AUTHORS (9)
ABSTRACT
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.
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