An interaction between the III-IV linker and CTD in NaV1.5 confers regulation of inactivation by CaM and FHF.

TitleAn interaction between the III-IV linker and CTD in NaV1.5 confers regulation of inactivation by CaM and FHF.
Publication TypeJournal Article
Year of Publication2020
AuthorsGade, AR, Marx, SO, Pitt, GS
JournalJ Gen Physiol
Volume152
Issue2
Date Published2020 Feb 03
ISSN1540-7748
Abstract

Voltage gated sodium channel (VGSC) activation drives the action potential upstroke in cardiac myocytes, skeletal muscles, and neurons. After opening, VGSCs rapidly enter a non-conducting, inactivated state. Impaired inactivation causes persistent inward current and underlies cardiac arrhythmias. VGSC auxiliary proteins calmodulin (CaM) and fibroblast growth factor homologous factors (FHFs) bind to the channel's C-terminal domain (CTD) and limit pathogenic persistent currents. The structural details and mechanisms mediating these effects are not clear. Building on recently published cryo-EM structures, we show that CaM and FHF limit persistent currents in the cardiac NaV1.5 VGSC by stabilizing an interaction between the channel's CTD and III-IV linker region. Perturbation of this intramolecular interaction increases persistent current and shifts the voltage dependence of steady-state inactivation. Interestingly, the NaV1.5 residues involved in the interaction are sites mutated in the arrhythmogenic long QT3 syndrome (LQT3). Along with electrophysiological investigations of this interaction, we present structural models that suggest how CaM and FHF stabilize the interaction and thereby limit the persistent current. The critical residues at the interaction site are conserved among VGSC isoforms, and subtle substitutions provide an explanation for differences in inactivation among the isoforms.

DOI10.1085/jgp.201912434
Alternate JournalJ. Gen. Physiol.
PubMed ID31865383
PubMed Central IDPMC7062510
Grant ListR01 HL071165 / HL / NHLBI NIH HHS / United States
R01 HL112918 / HL / NHLBI NIH HHS / United States
R01 HL122967 / HL / NHLBI NIH HHS / United States