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Long-QT syndrome-associated caveolin-3 mutations differentially regulate the hyperpolarization-activated cyclic nucleotide gated channel 4.
Motloch, L J; Larbig, R; Darabi, T; Reda, S; Motloch, K A; Wernly, B; Lichtenauer, M; Gebing, T; Schwaiger, A; Zagidullin, N; Wolny, M; Hoppe, U C.
Afiliación
  • Motloch LJ; Department of Internal Medicine II, Paracelsus Medical University , Salzburg, Austria.
  • Larbig R; Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital Muenster , Muenster, Germany.
  • Darabi T; Department of Internal Medicine II, Paracelsus Medical University , Salzburg, Austria.
  • Reda S; Department of Internal Medicine II, Paracelsus Medical University , Salzburg, Austria.
  • Motloch KA; Research Program for Ophthalmology and Glaucoma Research, University Clinic of Ophthalmology and Optometry, Paracelsus Medical University/SALK , Salzburg, Austria.
  • Wernly B; Department of Internal Medicine II, Paracelsus Medical University , Salzburg, Austria.
  • Lichtenauer M; Department of Internal Medicine II, Paracelsus Medical University , Salzburg, Austria.
  • Gebing T; Department of Internal Medicine II, Paracelsus Medical University , Salzburg, Austria.
  • Schwaiger A; Department of Internal Medicine II, Paracelsus Medical University , Salzburg, Austria.
  • Zagidullin N; Department of Internal Diseases, Bashkir State Medical University , Ufa, Russia.
  • Wolny M; Department of Internal Medicine II, Paracelsus Medical University , Salzburg, Austria.
  • Hoppe UC; Department of Internal Medicine II, Paracelsus Medical University , Salzburg, Austria.
Physiol Int ; 104(2): 130-138, 2017 Jun 01.
Article en En | MEDLINE | ID: mdl-28648120
Background Caveolin-3 (cav-3) mutations are linked to the long-QT syndrome (LQTS) causing distinct clinical symptoms. Hyperpolarization-activated cyclic nucleotide channel 4 (HCN4) underlies the pacemaker current If. It associates with cav-3 and both form a macromolecular complex. Methods To examine the effects of human LQTS-associated cav-3 mutations on HCN4-channel function, HEK293-cells were cotransfected with HCN4 and wild-type (WT) cav-3 or a LQTS-associated cav-3 mutant (T78M, A85T, S141R, or F97C). HCN4 currents were recorded using the whole-cell patch-clamp technique. Results WT cav-3 significantly decreased HCN4 current density and shifted midpoint of activation into negative direction. HCN4 current properties were differentially modulated by LQTS-associated cav-3 mutations. When compared with WT cav-3, A85T, F97C, and T78M did not alter the specific effect of cav-3, but S141R significantly increased HCN4 current density. Compared with WT cav-3, no significant modifications of voltage dependence of steady-state activation curves were observed. However, while WT cav-3 alone had no significant effect on HCN4 current activation, all LQTS-associated cav-3 mutations significantly accelerated HCN4 activation kinetics. Conclusions Our results indicate that HCN4 channel function is modulated by cav-3. LQTS-associated mutations of cav-3 differentially influence pacemaker current properties indicating a pathophysiological role in clinical manifestations.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de QT Prolongado / Potenciales de Acción / Canales de Potasio / Caveolina 3 / Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización / Proteínas Musculares Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: Physiol Int Año: 2017 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Hungria
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de QT Prolongado / Potenciales de Acción / Canales de Potasio / Caveolina 3 / Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización / Proteínas Musculares Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: Physiol Int Año: 2017 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Hungria