Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito

The Ca(2+)-independent transient outward K(+) current (I(to)) plays an important electrophysiological role in normal and diseased hearts. However, its contribution to ventricular repolarization remains controversial because of differences in its phenotypic expression and function across species. The dog, a frequently used model of human cardiac disease, exhibits altered functional expression of I(to). To better understand the relevance of electrical remodeling in dogs to humans, we studied the phenotypic differences in ventricular I(to) of both species with electrophysiological, pharmacological, and protein-chemical techniques. Several notable distinctions were elucidated, including slower current decay, more rapid recovery from inactivation, and a depolarizing shift of steady-state inactivation in human vs. canine I(to). Whereas recovery from inactivation of human I(to) followed a monoexponential time course, canine I(to) recovered with biexponential kinetics. Pharmacological sensitivity to flecainide was markedly greater in human than canine I(to), and exposure to oxidative stress did not alter the inactivation kinetics of I(to) in either species. Western blot analysis revealed immunoreactive bands specific for Kv4.3, Kv1.4, and Kv channel-interacting protein (KChIP)2 in dog and human, but with notable differences in band sizes across species. We report for the first time major variations in phenotypic properties of human and canine ventricular I(to) despite the presence of the same subunit proteins in both species. These data suggest that differences in electrophysiological and pharmacological properties of I(to) between humans and dogs are not caused by differential expression of the K channel subunit genes thought to encode I(to), but rather may arise from differences in molecular structure and/or posttranslational modification of these subunits.