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Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate

The opening and closing of voltage-dependent potassium channels is dependent on a tight coupling between movement of the voltage sensing S4 segments and the activation gate. A specific interaction between intracellular amino- and carboxyl-termini is required for the characteristically slow rate of c...

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Detalles Bibliográficos
Autores principales: Zangerl-Plessl, Eva-Maria, Wu, Wei, Sanguinetti, Michael C., Stary-Weinzinger, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9996038/
https://www.ncbi.nlm.nih.gov/pubmed/36911523
http://dx.doi.org/10.3389/fmolb.2023.1137368
Descripción
Sumario:The opening and closing of voltage-dependent potassium channels is dependent on a tight coupling between movement of the voltage sensing S4 segments and the activation gate. A specific interaction between intracellular amino- and carboxyl-termini is required for the characteristically slow rate of channel closure (deactivation) of hERG1 channels. Compounds that increase hERG1 channel currents represent a novel approach for prevention of arrhythmia associated with prolonged ventricular repolarization. RPR260243 (RPR), a quinoline oxo-propyl piperidine derivative, inhibits inactivation and dramatically slows the rate of hERG1 channel deactivation. Here we report that similar to its effect on wild-type channels, RPR greatly slows the deactivation rate of hERG1 channels missing their amino-termini, or of split channels lacking a covalent link between the voltage sensor domain and the pore domain. By contrast, RPR did not slow deactivation of C-terminal truncated hERG1 channels or D540K hERG1 mutant channels activated by hyperpolarization. Together, these findings indicate that ability of RPR to slow deactivation requires an intact C-terminus, does not slow deactivation by stabilizing an interaction involving the amino-terminus or require a covalent link between the voltage sensor and pore domains. All-atom molecular dynamics simulations using the cryo-EM structure of the hERG1 channel revealed that RPR binds to a pocket located at the intracellular ends of helices S5 and S6 of a single subunit. The slowing of channel deactivation by RPR may be mediated by disruption of normal S5-S6 interactions.