Nakajima T, et al. (2007) HERG is protected from pharmacological block by alpha-1,2-glucosyltransferase function. J Biol Chem 282(8):5506-13
Abstract: The HERG 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 U.S. Food and Drug Administration. Hence, an improved understanding of the regulatory factors that protect most individuals from aLQTS is essential to advancing clinical therapeutics in broad areas, from cancer chemotherapy to antipsychotics and antidepressants. Here, we show that the K(+) channel regulatory protein 1 (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 diminishes HERG blockade by dofetilide. Inhibition of cellular glycosylation pathways with tunicamycin abrogated the effects of KCR1, as did expression in lec-1 cells deficient in glycosylation. Moreover, KCR1 complements the growth defect of an alg10 deficient yeast strain, and enhances glycosylation of an ALG10 substrate in yeast. HERG itself is not the target for KCR1-mediated glycosylation, since the dofetilide response of glycosylation deficient HERG(N598Q) is 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 indicates that KCR1 expression is protective against arrhythmias. These findings reveal a potential new avenue for targeted prevention of the aLQTS.
|Status: Published||Type: Journal Article||PubMed ID: 17189275|
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