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Functional characterization of CaVα2δ mutations associated with sudden cardiac death.
Bourdin, Benoîte; Shakeri, Behzad; Tétreault, Marie-Philippe; Sauvé, Rémy; Lesage, Sylvie; Parent, Lucie.
Afiliação
  • Bourdin B; From the Département de Physiologie, Montreal Heart Institute Research Centre, and.
  • Shakeri B; From the Département de Physiologie, Montreal Heart Institute Research Centre, and.
  • Tétreault MP; From the Département de Physiologie, Montreal Heart Institute Research Centre, and.
  • Sauvé R; From the Département de Physiologie, Montreal Heart Institute Research Centre, and.
  • Lesage S; Département de Microbiologie, Infectiologie et Immunologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
  • Parent L; From the Département de Physiologie, Montreal Heart Institute Research Centre, and lucie.parent@umontreal.ca.
J Biol Chem ; 290(5): 2854-69, 2015 Jan 30.
Article em En | MEDLINE | ID: mdl-25527503
ABSTRACT
L-type Ca(2+) channels play a critical role in cardiac rhythmicity. These ion channels are oligomeric complexes formed by the pore-forming CaVα1 with the auxiliary CaVß and CaVα2δ subunits. CaVα2δ increases the peak current density and improves the voltage-dependent activation gating of CaV1.2 channels without increasing the surface expression of the CaVα1 subunit. The functional impact of genetic variants of CACNA2D1 (the gene encoding for CaVα2δ), associated with shorter repolarization QT intervals (the time interval between the Q and the T waves on the cardiac electrocardiogram), was investigated after recombinant expression of the full complement of L-type CaV1.2 subunits in human embryonic kidney 293 cells. By performing side-by-side high resolution flow cytometry assays and whole-cell patch clamp recordings, we revealed that the surface density of the CaVα2δ wild-type protein correlates with the peak current density. Furthermore, the cell surface density of CaVα2δ mutants S755T, Q917H, and S956T was not significantly different from the cell surface density of the CaVα2δ wild-type protein expressed under the same conditions. In contrast, the cell surface expression of CaVα2δ D550Y, CaVα2δ S709N, and the double mutant D550Y/Q917H was reduced, respectively, by ≈30-33% for the single mutants and by 60% for the latter. The cell surface density of D550Y/Q917H was more significantly impaired than protein stability, suggesting that surface trafficking of CaVα2δ was disrupted by the double mutation. Co-expression with D550Y/Q917H significantly decreased CaV1.2 currents as compared with results obtained with CaVα2δ wild type. It is concluded that D550Y/Q917H reduced inward Ca(2+) currents through a defect in the cell surface trafficking of CaVα2δ. Altogether, our results provide novel insight in the molecular mechanism underlying the modulation of CaV1.2 currents by CaVα2δ.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Morte Súbita Cardíaca / Mutação de Sentido Incorreto / Canais de Cálcio Tipo L Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Morte Súbita Cardíaca / Mutação de Sentido Incorreto / Canais de Cálcio Tipo L Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2015 Tipo de documento: Article