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Am J Physiol Cell Physiol 286: C1453-C1463, 2004. First published February 4, 2004; doi:10.1152/ajpcell.00275.2003
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Protein and Vesicle Trafficking, Cytoskeleton

An LQT mutant minK alters KvLQT1 trafficking

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

Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461

Submitted 26 January 2003 ; accepted in final form 30 January 2004

Cardiac IKs, 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 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 {alpha}-subunit.

potassium channel; hereditary arrhythmia; electrophysiology; protein interaction


Address for reprint requests and other correspondence: T. V. McDonald, Depts. of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461 (E-mail: mcdonald{at}aecom.yu.edu).




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