Structural basis for gating pore current in periodic paralysis.

Nature
Daohua JiangWilliam A Catterall

Abstract

Potassium-sensitive hypokalaemic and normokalaemic periodic paralysis are inherited skeletal muscle diseases characterized by episodes of flaccid muscle weakness1,2. They are caused by single mutations in positively charged residues ('gating charges') in the S4 transmembrane segment of the voltage sensor of the voltage-gated sodium channel Nav1.4 or the calcium channel Cav1.11,2. Mutations of the outermost gating charges (R1 and R2) cause hypokalaemic periodic paralysis1,2 by creating a pathogenic gating pore in the voltage sensor through which cations leak in the resting state3,4. Mutations of the third gating charge (R3) cause normokalaemic periodic paralysis 5 owing to cation leak in both activated and inactivated states 6 . Here we present high-resolution structures of the model bacterial sodium channel NavAb with the analogous gating-charge mutations7,8, which have similar functional effects as in the human channels. The R2G and R3G mutations have no effect on the backbone structures of the voltage sensor, but they create an aqueous cavity near the hydrophobic constriction site that controls gating charge movement through the voltage sensor. The R3G mutation extends the extracellular aqueous cleft through the entire length...Continue Reading

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Citations

Nov 23, 2018·Channels·Alexandra PinggeraJörg Striessnig
Apr 9, 2020·Toxins·YanYan ChuRiLei Yu
Sep 21, 2019·Annual Review of Pharmacology and Toxicology·William A CatterallTamer M Gamal El-Din
Mar 18, 2020·Frontiers in Pharmacology·James R Groome, Landon Bayless-Edwards
Jun 26, 2020·Pflügers Archiv : European journal of physiology·Nadine J OrtnerJörg Striessnig
Oct 26, 2018·Frontiers in Cardiovascular Medicine·Adrien Moreau, Mohamed Chahine
Dec 24, 2019·Cell·Daohua JiangWilliam A Catterall
Sep 12, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Laura SoléMichael M Tamkun
Feb 12, 2021·Journal of Chemical Information and Modeling·Giulio AlberiniLuca Maragliano
Mar 27, 2021·Physiological Reviews·Massimo MantegazzaWilliam A Catterall
Apr 10, 2021·The Journal of General Physiology·Mohammad-Reza GhovanlooPeter C Ruben
Feb 14, 2019·Chemical Reviews·Valentina CorradiD Peter Tieleman
Nov 4, 2021·Proceedings of the National Academy of Sciences of the United States of America·Tamer M Gamal El-DinWilliam A Catterall

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