An LQT mutant minK alters KvLQT1 trafficking

Andrew Krumerman, Xiaohong Gao, Jin Song Bian, Yonathan F. Melman, Anna Kagan, Thomas V. McDonald

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Cardiac IKs, the slowly activated delayed-rectifier K + current, is produced by the protein complex composed of α- and β-subunits: KvLQT1 and minK. Mutations of genes encoding KvLQT1 and minK are responsible for the hereditary long QT syndrome (loci LQT1 and LQT5, respectively). MinK-L51H fails to traffic to the cell surface, thereby failing to produce effective IKs. We examined the effects that minK-L51H and an endoplasmic reticulum (ER)-targeted minK (minK-ER) exerted over the electrophysiology and biosynthesis of coexpressed KvLQT1. Both minK-L51H and minK-ER were sequestered primarily in the ER as confirmed by lack of plasma membrane expression. Glycosylation and immunofluorescence patterns of minK-L51H were qualitatively different for minK-ER, suggesting differences in trafficking. Cotransfection with the minK mutants resulted in reduced surface expression of KvLQT1 as assayed by whole cell voltage clamp and immunofluorescence. MinK-L51H reduced current amplitude by 91% compared with wild-type (WT) minK/KvLQT1, and the residual current was identical to KvLQT1 without minK. The phenotype of minK-L51H on IKs was not dominant because coexpressed WT minK rescued the current and surface expression. Collectively, our data suggest that ER quality control prevents minK-L51H/KvLQT1 complexes from trafficking to the plasma membrane, resulting in decreased IKs. This is the first demonstration that a minK LQT mutation is capable of conferring trafficking defects onto its associated α-subunit.

Original languageEnglish (US)
Pages (from-to)C1453-C1463
JournalAmerican Journal of Physiology - Cell Physiology
Volume286
Issue number6 55-6
DOIs
StatePublished - Jun 1 2004

Keywords

  • Electrophysiology
  • Hereditary arrhythmia
  • Potassium channel
  • Protein interaction

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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    Krumerman, A., Gao, X., Bian, J. S., Melman, Y. F., Kagan, A., & McDonald, T. V. (2004). An LQT mutant minK alters KvLQT1 trafficking. American Journal of Physiology - Cell Physiology, 286(6 55-6), C1453-C1463. https://doi.org/10.1152/ajpcell.00275.2003