Molecular determinants of cardiac transient outward potassium current (Ito) expression and regulation

Rapidly activating and inactivating cardiac transient outward K⁺ currents, I_to, are expressed in most mammalian cardiomyocytes, and contribute importantly to the early phase of action potential repolarization and to plateau potentials. The rapidly recovering (I_to,f) and slowly recovering (I_to,s) components are differentially expressed in the myocardium, contributing to regional heterogeneities in action potential waveforms. Consistent with the marked differences in biophysical properties, distinct pore-forming (α) subunits underlie the two I_to components: Kv4.3/Kv4.2 subunits encode I_to,f, whereas Kv1.4 encodes I_to,s, channels. It has also become increasingly clear that cardiac I_to channels function as components of macromolecular protein complexes, comprising (four) Kvα subunits and a variety of accessory subunits and regulatory proteins that influence channel expression, biophysical properties and interactions with the actin cytoskeleton, and contribute to the generation of normal cardiac rhythms. Derangements in the expression or the regulation of I_to channels in inherited or acquired cardiac diseases would be expected to increase the risk of potentially life-threatening cardiac arrhythmias. Indeed, a recently identified Brugada syndrome mutation in KCNE3 (MiRP2) has been suggested to result in increased I_to,f densities. Continued focus in this area seems certain to provide new and fundamentally important insights into the molecular determinants of functional I_to channels and into the molecular mechanisms involved in the dynamic regulation of I_to channel functioning in the normal and diseased myocardium.