The 1997 Stevenson Award Lecture. Cardiac K+ channel gating: cloned delayed rectifier mechanisms and drug modulation

Abstract

K+ channels are ubiquitous membrane proteins, which have a central role in the control of cell excitability. In the heart, voltage-gated delayed rectifier K+ channels, like Kv1.5, determine repolarization and the cardiac action potential plateau duration. Here we review the broader properties of cloned voltage-gated K+ channels with specific reference to the hKv1.5 channel in heart. We discuss the basic structural components of K+ channels such as the pore, voltage sensor, and fast inactivation, all of which have been extensively studied. Slow, or C-type, inactivation and the structural features that control pore opening are less well understood, although recent studies have given new insight into these problems. Information about channel transitions that occur prior to opening is provided by gating currents, which reflect charge-carrying transitions between kinetic closed states. By studying modulation of the gating properties of K+ channels by cations and with drugs, we can make a more complete interpretation of the state dependence of drug and ion interactions with the channel. In this way we can uncover the detailed mechanisms of action of K+ channel blockers such as tetraethylammonium ions and 4-aminopyridine, and antiarrhythmic agents such as nifedipine and quinidine.