title: HERG is protected from pharmacological block by alpha-1,2-glucosyltransferase function.
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.
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakajima
authors.forename: Kenshi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Prakash C
authors.initials: PC
authors.lastname: Viswanathan
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Mircea
authors.initials: M
authors.lastname: Anghelescu
authors.forename: Kate A
authors.initials: KA
authors.lastname: Barksdale
authors.forename: Wen
authors.initials: W
authors.lastname: Shuai
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Balser
authors.forename: Sabina
authors.initials: S
authors.lastname: Kupershmidt
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000009:adverse effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005964:Glucosyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D008955:Models, Cardiovascular; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy; D046188:Protein Modification, Translational / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics
chemical_list: D000928:Antidepressive Agents; D000970:Antineoplastic Agents; D014150:Antipsychotic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D029701:Saccharomyces cerevisiae Proteins; C518821:ALG10B protein, human; C113849:DIE2 protein, S cerevisiae; D005964:Glucosyltransferases