Structural Advances in Voltage-Gated Sodium Channels

Abstract

Voltage-gated sodium (NaV) channels are responsible for the rapid rising-phase of action potentials in excitable cells. Over 1,000 mutations in NaV channels are associated with human diseases including epilepsy, periodic paralysis, arrhythmias and pain disorders. Natural toxins and clinically-used small-molecule drugs bind to NaV channels and modulate their functions. Recent advances from cryo-electron microscopy (cryo-EM) structures of NaV channels reveal invaluable insights into the architecture, activation, fast inactivation, electromechanical coupling, ligand modulation and pharmacology of eukaryotic NaV channels. These structural analyses not only demonstrate molecular mechanisms for NaV channel structure and function, but also provide atomic level templates for rational development of potential subtype-selective therapeutics. In this review, we summarize recent structural advances of eukaryotic NaV channels, highlighting the structural features of eukaryotic NaV channels as well as distinct modulation mechanisms by a wide range of modulators from natural toxins to synthetic small-molecules.

Inhibition of Voltage-Gated Na+ Currents Exerted by KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea), an Inhibitor of Na+-Ca2+ Exchanging Process

“…Moreover, in cultured hippocampal neurons, KB-R7943 exhibits neuroprotection from glutamate-induced excitotoxicity by blocking NMDA receptor-mediated activity (IC 50 = 13.4 μM) as well as by inhibiting complex I in the mitochondrial respiratory chain (IC 50 = 11.4 μM) [ 8 ]. Under this scenario, the inhibitory effect of this compound on the magnitude and gating of I Na could be of mechanistic, pharmacological, or even clinical relevance [ 15 , 16 , 70 ].…”

“…The NCX activity could be indirectly altered by changes in the magnitude of voltage-gated Na + current ( I Na ) [ 3 , 5 , 6 ]. Therefore, it is worthwhile to reappraise the ionic mechanism of KB-R7943 actions which may exist in different types of ionic currents, particularly at I Na , because significant modifications in magnitude and gating kinetics of this current have been recently investigated for their therapeutic or pharmacological effectiveness [ 11 , 12 , 13 , 14 , 15 , 16 ].…”

Inhibitory Effects of Nobiletin on Voltage-Gated Na+ Channel in Rat Ventricular Myocytes Based on Electrophysiological Analysis and Molecular Docking Method

“…The sequence alignments of rNav1.5 (Uniprot ID: P15389) and hNa V 1.5 (Uniprot ID: Q14524) are compared in Figure S2 and exhibit more than 94% similarity. The open state structure of rNav1.5 was achieved by importing the IFM/QQQ mutations to remove the fast inactivation gate [ 28 ].…”

Advances in Ion Channel, Non-Desmosomal Variants and Autophagic Mechanisms Implicated in Arrhythmogenic Cardiomyopathy

“…Nav channels perform an essential and fundamental role in the transmission of electrical signals [ 20 ]. Nav is currently classified in the field of pharmacological research as subtypes 1.1–1.9, of which 1.4 and 1.5 are predominantly found on cardiac myocytes.…”

“…Even though there are currently laboratory results indicating that exosomes can improve ACM cardiac fibrosis in Dsg-2 mutant mice [ 18 ], these are only preclinical studies and the current clinical management of ACM patients is still at the stage of traditional optimization of anti-heart failure, prevention of arrhythmogenesis and other evidence-based drugs to improve the quality of life of patients [ 19 ]. SCN5A is the gene encoding Nav1.5, while the structure of the complex formed by Nav1.5 in voltage-gated sodium channels (Nav) with the antiarrhythmic drugs flecainide, propafenone and quinidine show the binding site of the antiarrhythmic drug in the centrum [ 20 ]. Variants in the SCN5A gene were also reported in studies related to the ACM [ 21 ].…”