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Intracellular potassium stabilizes human ether-à-go-go-related gene channels for export from endoplasmic reticulum.
Wang, Lu; Dennis, Adrienne T; Trieu, Phan; Charron, Francois; Ethier, Natalie; Hebert, Terence E; Wan, Xiaoping; Ficker, Eckhard.
Afiliación
  • Wang L; Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109, USA.
Mol Pharmacol ; 75(4): 927-37, 2009 Apr.
Article en En | MEDLINE | ID: mdl-19139152
Several therapeutic compounds have been identified that prolong the QT interval on the electrocardiogram and cause torsade de pointes arrhythmias not by direct block of the cardiac potassium channel human ether-à-go-go-related gene (hERG) but via disruption of hERG trafficking to the cell surface membrane. One example of a clinically important compound class that potently inhibits hERG trafficking are cardiac glycosides. We have shown previously that inhibition of hERG trafficking by cardiac glycosides is initiated via direct block of Na(+)/K(+) pumps and not via off-target interactions with hERG or any other protein. However, it was not known how pump inhibition at the cell surface is coupled to hERG processing in the endoplasmic reticulum. Here, we show that depletion of intracellular K(+)-either indirectly after long-term exposure to cardiac glycosides or directly after exposure to gramicidin in low sodium media-is sufficient to disrupt hERG trafficking. In K(+)-depleted cells, hERG trafficking can be restored by permeating K(+) or Rb(+) ions, incubation at low temperature, exposure to the pharmacological chaperone astemizole, or specific mutations in the selectivity filter of hERG. Our data suggest a novel mechanism for drug-induced trafficking inhibition in which cardiac glycosides produce a [K(+)](i)-mediated conformational defect directly in the hERG channel protein.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Potasio / Retículo Endoplásmico / Canales de Potasio Éter-A-Go-Go / Líquido Intracelular Límite: Humans Idioma: En Revista: Mol Pharmacol Año: 2009 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Potasio / Retículo Endoplásmico / Canales de Potasio Éter-A-Go-Go / Líquido Intracelular Límite: Humans Idioma: En Revista: Mol Pharmacol Año: 2009 Tipo del documento: Article País de afiliación: Estados Unidos