Abstract

The HERG (human ether-à-go-go-related gene) protein, which underlies the cardiac repolarizing current I(Kr), is the unintended target for many pharmaceutical agents. Inadvertent block of I(Kr), 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 I(Kr) drug sensitivity, protects HERG through glucosyltransferase function. KCR1 and the yeast alpha-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 alpha-1,2-glucosyltransferase function is a key component of the molecular pathway whereby KCR1 diminishes I(Kr) 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.

Highlights

  • (LQT2) of the congenital long QT syndrome (LQTS),2 an arrhythmia syndrome characterized by action potential prolongation and delayed cardiac repolarization

  • To test whether KCR1 and Alg10 share functional characteristics in mammalian cells, we examined whether Alg10, like KCR1 [16], modulates drug block of IHERG

  • The most frequent cause of acquired form of LQTS (aLQTS) is the unintended block of IKr by commonly used pharmaceutical agents [7, 36], leading to impaired repolarization of cardiac myocytes, action potential prolongation, and potentially fatal ventricular arrhythmias

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Summary

Introduction

(LQT2) of the congenital long QT syndrome (LQTS),2 an arrhythmia syndrome characterized by action potential prolongation and delayed cardiac repolarization. N-linked glycosylation is a requirement for the KCR1-mediated modulation of drug block of IHERG, the KCR1 effect should not be observed in Lec1 cells.

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