An LQT mutant minK alters KvLQT1 trafficking

Am J Physiol Cell Physiol. 2004 Jun;286(6):C1453-63. doi: 10.1152/ajpcell.00275.2003. Epub 2004 Feb 4.


Cardiac I(Ks), the slowly activated delayed-rectifier K(+) current, is produced by the protein complex composed of alpha- and beta-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 I(Ks). 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 I(Ks) 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 I(Ks). This is the first demonstration that a minK LQT mutation is capable of conferring trafficking defects onto its associated alpha-subunit.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cell Compartmentation / genetics
  • Cell Membrane / metabolism*
  • Cricetinae
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Heart Ventricles / metabolism
  • Heart Ventricles / physiopathology
  • Humans
  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / metabolism
  • Long QT Syndrome / physiopathology
  • Membrane Potentials / genetics
  • Mutation / genetics
  • Myocytes, Cardiac / metabolism
  • Patch-Clamp Techniques
  • Potassium Channels / genetics*
  • Potassium Channels / metabolism*
  • Potassium Channels, Voltage-Gated*
  • Protein Binding / genetics
  • Protein Transport / genetics


  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • Potassium Channels
  • Potassium Channels, Voltage-Gated