Reduced Transient Outward K + Current and Cardiac Hypertrophy

Abstract

Action potentials coordinate contraction and relaxation of the heart. The long plateau phase of the action potential ensures sufficient Ca2+ entry into the cytoplasm via L-type Ca2+ channels to invoke Ca2+-induced Ca2+ release from the sarcoplasmic reticulum and activation of the contractile filaments. Action potentials are initiated by opening of voltage-gated Na+ channels that in turn rapidly depolarize the membrane and open voltage-gated Ca2+ and K+ channels. Some K+ channels activate immediately in response to depolarization, then inactivate within tens of milliseconds later, and mediate a current called the transient outward K+ current ( I to). In many mammalian hearts, including human, I to is responsible for the initial rapid phase of action potential repolarization, discernible as a notch preceding the plateau phase, but has little role in terminal repolarization. In contrast, I to in rodents is a major repolarizing current throughout the comparatively short cardiac action potential (Figure, panel A) necessary to maintain extremely high heart rates. I to is composed of at least two components in the mammalian ventricle. One component is characterized by a slow recovery from inactivation ( I tos), another by a relatively fast recovery from inactivation ( I tof). Comparison of native currents and heterologously expressed channels indicates that I tof is mediated by Kv4.2 and/or Kv4.3 channels, whereas I tos is mediated by Kv1.4 channels. Reduction of I tof prolongs APD and may induce hypertrophy via a calcineurin-dependent signaling pathway. A, At physiologically relevant heart rates, I tof is the major repolarizing current of the ventricular action potential in rodents. Pharmacological block of I tof or functional knockout of Kv4.2 channel subunits lengthens the plateau phase of the action potential. B, Reduction of I tof (Kv4.2 channels) but not I tos (Kv1.4 channels) prolongs action …