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Cell Rep ; 25(6): 1610-1621.e5, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30404013

RESUMO

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.


Assuntos
Canais de Cálcio Tipo N/metabolismo , Canais de Cálcio/metabolismo , Membrana Celular/metabolismo , Ativação do Canal Iônico , Proteínas de Membrana/metabolismo , Animais , Canais de Cálcio/genética , Canais de Cálcio Tipo N/genética , Hipocampo/metabolismo , Masculino , Mutação/genética , Neuritos/metabolismo , Ligação Proteica , Ratos Sprague-Dawley
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