Transient outward potassium current and Ca2+ homeostasis in the heart:: beyond the action potential

The present review deals with Ca2+-independent, K+-carried transient outward current (I-to), an important determinant of the early repolarization phase of the myocardial action potential. The density of total I-to and of its fast and slow components (I-to,I-f and I-to,I-s, respectively), as well as the expression of their molecular correlates (pore-forming protein isoforms Kv4.3/4.2 and Kv1.4, respectively), vary during postnatal development and aging across species and regions of the heart. Changes in I-to may also occur in disease conditions, which may affect the profile of cardiac repolarization and vulnerability to arrhythmas, and also influence excitation-contraction coupling. Decreased I-to density, observed in immature and aging myocardium, as well as during several types of cardiomyopathy and heart failure, may be associated with action potential prolongation, which favors Ca2+ influx during membrane depolarization and limits voltage-dependent Ca2+ efflux via the Na+/Ca2+ exchanger. Both effects contribute to increasing sarcoplasmic reticulum (SR) Ca2+ content (the main source of contraction-activating Ca2+ in mammalian myocardium), which, in addition to the increased Ca2+ influx, should enhance the amount of Ca2+ released by the SR during systole. This change usually takes place under conditions in which SR function is depressed, and may be adaptive since it provides partial compensation for SR deficiency, although possibly at the cost of asynchronous SR Ca2+ release and greater propensity to triggered arrhythmias. Thus, I-to modulation appears to be an additional mechanism by which excitation-contraction coupling in myocardial cells is indirectly regulated.