Low-Affinity Polyamine Block of IK1 Facilitating the Cardiac Repolarization

Abstract

The inward rectifier K+ currents play an important role in cardiac repolarization. We have studied the blockage of Kir2 channels by polyamines and Mg2+ in detail to clarify the precise mechanisms that determine the voltage- and time-dependences of the cardiac strong inward rectifier K+ current, IK1, during repolarization. Our studies suggested that a large portion of the time-independent component of IK1, which flows at membrane potentials near the resting potential, is carried by a small (7–10%) conductance susceptible only to the low-affinity mode of blockage by intracellular polyamines. An “IK1 transient” caused by the relief of the Mg2+ block of IK1 during early phase 3 appeared to flow through the conductance susceptible to the high-affinity mode of the polyamine block. The fractional conductances showing distinct sensitivities to the polyamine blockage varied in the presence of different concentrations of polyamines, suggesting that IK1 is modulated by intracellular polyamines in a complicated manner. The D172N mutation in the transmembrane pore region of Kir2.1, which has been proposed to increase IK1, thereby causing the short QT syndrome, made almost all of the channel conductance susceptible only to the low-affinity block. Our study suggests that modulation of the fractions of IK1 exhibiting distinct sensitivities to the polyamine/Mg2+ block may be a potential pharmacological target for treating abnormal cardiac repolarization.