Mechanistic basis for LQT1 caused by S3 mutations in the KCNQ1 subunit of IKs

Author:

Eldstrom Jodene1,Xu Hongjian1,Werry Daniel1,Kang Congbao2,Loewen Matthew E.1,Degenhardt Amanda1,Sanatani Shubhayan1,Tibbits Glen F.3,Sanders Charles2,Fedida David1

Affiliation:

1. Department of Anesthesiology, Pharmacology and Therapeutics, and Department of Pediatrics, Children and Women’s Hospital, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

2. Department of Biochemistry, Vanderbilt University, Nashville, TN 37235

3. Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada

Abstract

Long QT interval syndrome (LQTS) type 1 (LQT1) has been reported to arise from mutations in the S3 domain of KCNQ1, but none of the seven S3 mutations in the literature have been characterized with respect to trafficking or biophysical deficiencies. Surface channel expression was studied using a proteinase K assay for KCNQ1 D202H/N, I204F/M, V205M, S209F, and V215M coexpressed with KCNE1 in mammalian cells. In each case, the majority of synthesized channel was found at the surface, but mutant IKs current density at +100 mV was reduced significantly for S209F, which showed ∼75% reduction over wild type (WT). All mutants except S209F showed positively shifted V1/2’s of activation and slowed channel activation compared with WT (V1/2 = +17.7 ± 2.4 mV and τactivation of 729 ms at +20 mV; n = 18). Deactivation was also accelerated in all mutants versus WT (126 ± 8 ms at −50 mV; n = 27), and these changes led to marked loss of repolarizing currents during action potential clamps at 2 and 4 Hz, except again S209F. KCNQ1 models localize these naturally occurring S3 mutants to the surface of the helices facing the other voltage sensor transmembrane domains and highlight inter-residue interactions involved in activation gating. V207M, currently classified as a polymorphism and facing lipid in the model, was indistinguishable from WT IKs. We conclude that S3 mutants of KCNQ1 cause LQTS predominantly through biophysical effects on the gating of IKs, but some mutants also show protein stability/trafficking defects, which explains why the kinetic gain-of-function mutation S209F causes LQT1.

Publisher

Rockefeller University Press

Subject

Physiology

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