N-Glycosylation-dependent block is a novel mechanism for drug-induced cardiac arrhythmia

SPECIFIC AIMSIKr is an important repolarizing potassium current in the human ventricle. There is considerable evidence to support the hypothesis that the native channel is composed of the pore-forming subunit HERG and the β subunit, MiRP1. Genetic mutations in both genes are found in patients with congenital and acquired prolongation of the QT interval, which predisposes to a specific form of polymorphic ventricular tachycardia known as Long QT syndrome. Of particular interest is the case of a MiRP1 single-nucleotide polymorphism resulting in a T to A amino acid mutation at position 8, T8A, that is normal at baseline but able to impair MiRP1/HERG function if associated with the antibiotic sulfamethoxazole (SMX). This study was directed at investigating the molecular mechanism by which T8A susceptibility arrhythmia mutant causes SMX high-affinity block.PRINCIPAL FINDINGS1. MiRP1 protects HERG from the inhibitory effect of SMXOur first step toward the investigation of the molecular mechanisms determining SM...