Molecular interactions between two long-QT syndrome gene products, HERG and KCNE2, rationalized by in vitro and in silico analysis

The cardiac delayed rectifier potassium current mediates repolarization of the action potential and underlies the QT interval of the EGG. Mutations in either of the two molecular components of the rapid delayed rectifier (I-K ,I-r), HERG and KCNE2, have been linked to heritable or acquired long-QT sy ndrome. Mechanisms whereby mutations of KCNE2 produce fatal cardiac arrhyth mias characteristic of long-QT syndrome remain unclear. In this study, we c haracterize functional interactions between HERG and KCNE2 with a view to d efining underlying mechanisms for action potential prolongation and long-QT syndrome. Whereas coexpression of hKCNE2 with HERG alters both kinetics an d density of ionic current, incorporation of these effects into a quantitat ive model of the action potential predicts that only changes in current den sity significantly affect repolarization. Thus, the primary functional cons equence of hKCNE2 on action potential morphology is through modulation of I -K,I-r density, as predicted by the model. Mutations associated with long-Q T syndrome that result only in modest changes of gating kinetics may be epi phenomena or may modulate action potential repolarization via interaction w ith alternative pore-forming potassium channel a subunits.