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Am J Physiol Cell Physiol (February 4, 2004). doi:10.1152/ajpcell.00275.2003
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Submitted on July 2, 2003
Accepted on January 30, 2004

An LQT Mutant minK Alters KvLQT1 Trafficking

Andrew Krumerman1, Xiaohong Gao1, Jin-song Bian2, Yonathan F Melman1, Anne Kagan1, and Thomas V McDonald1*

1 Medicine & Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
2 Pharmacology, National University of Singapore, Singapore, Singapore

* To whom correspondence should be addressed. E-mail: mcdonald{at}aecom.yu.edu.

Cardiac IKs is produced by the protein complex comprised of {alpha}- and {beta}-subunits: KvLQT1 and minK. Mutations of genes encoding KvKQT1 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 ER-targeted minK (minK-ER) exerted over the electrophysiology and biosynthesis of co-expressed 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. Co-transfection 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 to WT minK/KvLQT1 and the residual current was identical to KvLQT1 without minK. The phenotype of minK-L51H on IKs were not dominant since co-expressed wild type minK (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.




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