A New Role for Calmodulin in Ion Channel Biology

Abstract

See related articles, pages 1048–1054 and 1055–1063 A time-dependent repolarizing current carried by outward movement of potassium ions was first identified by Hodgkin and Huxley, and has been recognized in heart since the 1960s.1,2 Experiments in the 1980s found that the amplitude of the current, then termed I K, increased when intracellular calcium was increased.3 The key advance to further understanding of the physiology of this important repolarizing current was the recognition in 1990 that it includes at least two distinct components, now termed I Kr and I Ks.4 These two currents have very different voltage-dependent gating behaviors and sensitivities to drugs and to activation of second messenger pathways. The amplitude and gating of I Ks is quite labile in experimental preparations and increases dramatically in response to activation of PKA.5–7 Such I Ks variability has been invoked as a mechanism underlying variability in the extent to which I Kr blockers prolong QT interval, a common problem in clinical medicine and drug development.7–10 At its simplest level, patients with robust I Ks display minimal QT prolongation with I Kr block, whereas those with I Ks reduction may display little QT prolongation at baseline but striking QT prolongation when I Kr, the major mechanism supporting normal repolarization in this setting, is blocked by drugs. Molecular genetic studies in the mid 1990s led to identification of the genes whose expression underlies these currents: I Kr is generated by expression of KCNH2 (initially termed HERG ), and I Ks is generated by the coexpression of a pore forming subunit, KCNQ1 (formerly termed KvLQT1 ), with important function modifying ancillary subunit KCNE1 (or minK).11 Mutations in KCNQ1 are the most common cause of type 1 long QT syndrome (LQT1). When mutations in KCNQ1 , KCNE1 , …