The molecular physiology of the cardiac transient outward potassium current (I_to) in normal and diseased myocardium

The Ca²⁺-independent transient outward potassium current (I_to) plays an important role in early repolarization of the cardiac action potential. I_tohas been clearly demonstrated in myocytes from different cardiac regions and species. Two kinetic variants of cardiac I_tohave been identified: fast I_to, called I_to.f, and slow I_to, called I_to.s. Recent findings suggest that I_to.fis formed by assembly of K_v4.2and/or K_v4.3alpha poreforming voltage-gated subunits while I_to.sis comprised of K_v1.4and possibly K_v1.7subunits. In addition, several regulatory subunits and pathways modulating the level and biophysical properties of cardiac I_tohave been identified. Experimental findings and data from computer modeling of cardiac action potentials have conclusively established an important physiological role of I_toin rodents, with its role in large mammals being less well defined due to complex interplay between a multitude of cardiac ionic currents. A central and consistent electrophysiological change in cardiac disease is the reduction in I_todensity with a loss of heterogeneity of I_toexpression and associated action potential prolongation. Alterations of I_toin rodent cardiac disease have been linked to repolarization abnormalities and alterations in intracellular Ca²⁺homeostasis, while in larger mammals the link with functional changes is far less certain. We review the current literature on the molecular basis for cardiac I_toand the functional consequences of changes in I_tothat occur in cardiovascular disease.