MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia

TLDR

MiRP1 is a small integral membrane subunit that assembles with HERG to form IKr channels with altered gating, conductance, and drug sensitivity. Mutations in MiRP1 produce IKr channels that activate slowly, deactivate rapidly, and exhibit reduced potassium currents and increased drug blockade, linking the gene to long‑QT syndrome, ventricular fibrillation, and clarithromycin‑induced arrhythmia.

Abstract

A novel potassium channel gene has been cloned, characterized, and associated with cardiac arrhythmia. The gene encodes MinK-related peptide 1 (MiRP1), a small integral membrane subunit that assembles with HERG, a pore-forming protein, to alter its function. Unlike channels formed only with HERG, mixed complexes resemble native cardiac IKr channels in their gating, unitary conductance, regulation by potassium, and distinctive biphasic inhibition by the class III antiarrhythmic E-4031. Three missense mutations associated with long QT syndrome and ventricular fibrillation are identified in the gene for MiRP1. Mutants form channels that open slowly and close rapidly, thereby diminishing potassium currents. One variant, associated with clarithromycin-induced arrhythmia, increases channel blockade by the antibiotic. A mechanism for acquired arrhythmia is revealed: genetically based reduction in potassium currents that remains clinically silent until combined with additional stressors.