Structure of the Cardiac Sodium Channel
| Autor: | William A. Catterall, Hui Shi, Yan Zhao, Daohua Jiang, Ning Zheng, Craig Yoshioka, Lige Tonggu, Tamer M. Gamal El-Din, Michael J. Lenaeus |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Patch-Clamp Techniques
Gating Voltage-Gated Sodium Channels Biology General Biochemistry Genetics and Molecular Biology Article Sodium Channels Cell Line Membrane Potentials NAV1.5 Voltage-Gated Sodium Channel 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Cheese medicine Moiety Animals Humans Glycosyl Receptor Flecainide 030304 developmental biology 0303 health sciences Sodium channel Sodium Cardiac action potential Heart Rats HEK293 Cells chemistry Mutation Biophysics Selectivity Ion Channel Gating 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Cell |
| ISSN: | 1097-4172 |
| Popis: | Summary Voltage-gated sodium channel Nav1.5 generates cardiac action potentials and initiates the heartbeat. Here, we report structures of NaV1.5 at 3.2–3.5 A resolution. NaV1.5 is distinguished from other sodium channels by a unique glycosyl moiety and loss of disulfide-bonding capability at the NaVβ subunit-interaction sites. The antiarrhythmic drug flecainide specifically targets the central cavity of the pore. The voltage sensors are partially activated, and the fast-inactivation gate is partially closed. Activation of the voltage sensor of Domain III allows binding of the isoleucine-phenylalanine-methionine (IFM) motif to the inactivation-gate receptor. Asp and Ala, in the selectivity motif DEKA, line the walls of the ion-selectivity filter, whereas Glu and Lys are in positions to accept and release Na+ ions via a charge-delocalization network. Arrhythmia mutation sites undergo large translocations during gating, providing a potential mechanism for pathogenic effects. Our results provide detailed insights into Nav1.5 structure, pharmacology, activation, inactivation, ion selectivity, and arrhythmias. |
| Databáze: | OpenAIRE |
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