Single-channel characteristics of wild-type I(Ks) channels and channels formed with two MinK mutants that cause long QT syndrome

Federico Sesti, Steve A.N. Goldstein

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179 Scopus citations

Abstract

I(Ks) channels are voltage dependent and K+ selective. They influence cardiac action potential duration through their contribution to myocyte repolarization. Assembled from mink and KvLQT1 subunits, I(Ks) channels are notable for a heteromeric ion conduction pathway in which both subunit types contribute to pore formation. This study was undertaken to assess the effects of mink on pore function. We first characterized the properties of wild-type human I(Ks) channels and channels formed only of KvLQT1 subunits. Channels were expressed in Xenopus laevis oocytes or Chinese hamster ovary cells and currents recorded in excised membrane patches or whole-cell mode. Unitary conductance estimates were dependent on bandwidth due to rapid channel 'flicker.' At 25 kHz in symmetrical 100-mM KCl, the single-channel conductance of I(Ks) channels was ~16 pS (corresponding to ~0.8 pA at 50 mV) as judged by noise-variance analysis; this was fourfold greater than the estimated conductance of homomeric KvLQT1 channels. Mutant I(Ks) channels formed with D76N and S74L mink subunits are associated with long QT syndrome. When compared with wild type, mutant channels showed lower unitary currents and diminished open probabilities with only minor changes in ion permeabilities. Apparently, the mutations altered single-channel currents at a site in the pore distinct from the ion selectivity apparatus. Patients carrying these mutant minK genes are expected to manifest decreased K+ flux through I(Ks) channels due to lowered single-channel conductance and altered gating.

Original languageEnglish (US)
Pages (from-to)651-663
Number of pages13
JournalJournal of General Physiology
Volume112
Issue number6
DOIs
StatePublished - 1998

All Science Journal Classification (ASJC) codes

  • Physiology

Keywords

  • Delayed rectifier
  • Heart
  • KvLQT1
  • Long QT syndrome
  • Potassium

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