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

The Ca²⁺-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.