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(t)(o,f)) and slowly recovering (I(t)(o,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 (alpha) subunits underlie the two I(t)(o) components: Kv4.3/Kv4.2 subunits
encode I(t)(o,f), whereas Kv1.4 encodes I(t)(o,s), channels. It has also become increasingly
clear that cardiac I(t)(o) channels function as components of macromolecular protein
complexes, comprising (four) Kvalpha 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(t)(o)
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(t)(o,f) densities. Continued focus in this area seems certain to provide new and
fundamentally important insights into the molecular determinants of functional I(t)(o)
channels and into the molecular mechanisms involved in the dynamic regulation of I(t)(o)
channel functioning in the normal and diseased myocardium.
Copyright 2009 Elsevier Inc. All rights reserved.