HERG is protected from pharmacological block by a-1,2- glucosyltransferase function

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The HERG (human ether-à -go-go-related gene) protein, which underlies the cardiac repolarizing current IKr, is the unintended target for many pharmaceutical agents. Inadvertent block of IKr, known as the acquired long QT syndrome (aLQTS), is a leading cause for drug withdrawal by the United States Food and Drug Administration. Hence, an improved understanding of the regulatory factors that protect most individuals from aLQTS is essential for advancing clinical therapeutics in broad areas, from cancer chemotherapy to antipsychotics and antidepressants. Here, we show that the K+ channel regulatory protein KCR1, which markedly reduces IKr drug sensitivity, protects HERG through glucosyltransferase function. KCR1 and the yeast a-1,2-glucosyltransferase ALG10 exhibit sequence homology, and like KCR1, ALG10 diminished HERG block by dofetilide. Inhibition of cellular glycosylation pathways with tunicamycin abrogated the effects of KCR1, as did expression in Lec1 cells (deficient in glycosylation). Moreover, KCR1 complemented the growth defect of an alg10-deficient yeast strain and enhanced glycosylation of an Alg10 substrate in yeast. HERG itself is not the target for KCR1-mediated glycosylation because the dofetilide response of glycosylation-deficient HERG(N598Q) was still modulated by KCR1. Nonetheless, our data indicate that the a-1,2-glucosyltransferase function is a key component of the molecular pathway whereby KCR1 diminishes IKr drug response. Incorporation of in vitro data into a computational model indicated that KCR1 expression is protective against arrhythmias. These findings reveal a potential new avenue for targeted prevention of aLQTS. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

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Journal of Biological Chemistry





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This article was published in Journal of Biological Chemistry, Volume 282, Issue 8, Pages 5506-5513.

The published version is available at http://dx.doi.org/10.1074/jbc.M605976200.

Copyright © 2007.

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