Gating control of the cardiac sodium channel Nav1.5 by its?3-subunit involves distinct roles for a transmembrane glutamic acid and the extracellular domain

Salvage, Samantha C. ✉; Zhu, Wandi; Habib, Zaki F.; Hwang, Soyon S.; Irons, Jennifer R.; Huang, Christopher L. H. ✉; Silva, Jonathan R. ✉; Jackson, Antony P. ✉

Angol nyelvű Tudományos Szakcikk (Folyóiratcikk)
Megjelent: JOURNAL OF BIOLOGICAL CHEMISTRY 0021-9258 1083-351X 294 (51) pp. 19752-19763 2019
  • SJR Scopus - Biochemistry: Q1
    The auxiliary ?3-subunit is an important functional regulator of the cardiac sodium channel Nav1.5, and some ?3 mutations predispose individuals to cardiac arrhythmias. The ?3-subunit uses its transmembrane ?-helix and extracellular domain to bind to Nav1.5. Here, we investigated the role of an unusually located and highly conserved glutamic acid (Glu-176) within the ?3 transmembrane region and its potential for functionally synergizing with the ?3 extracellular domain (ECD). We substituted Glu-176 with lysine (E176K) in the WT ?3-subunit and in a ?3-subunit lacking the ECD. Patch-clamp experiments indicated that the E176K substitution does not affect the previously observed ?3-dependent depolarizing shift of V-? of steady-state inactivation but does attenuate the accelerated recovery from inactivation conferred by the WT ?3-subunit. Removal of the ?3-ECD abrogated both the depolarizing shift of steady-state inactivation and the accelerated recovery, irrespective of the presence or absence of the Glu-176 residue. We found that steady-state inactivation and recovery from inactivation involve movements of the S4 helices within the DIII and DIV voltage sensors in response to membrane potential changes. Voltage-clamp fluorometry revealed that the E176K substitution alters DIII voltage sensor dynamics without affecting DIV. In contrast, removal of the ECD significantly altered the dynamics of both DIII and DIV. These results imply distinct roles for the ?3-Glu-176 residue and the ?3-ECD in regulating the conformational changes of the voltage sensors that determine channel inactivation and recovery from inactivation.
    Hivatkozás stílusok: IEEEACMAPAChicagoHarvardCSLMásolásNyomtatás
    2021-01-26 23:09