Cardiac SK channels: Friend or foe?

Abstract

Proper repolarization of cardiac action potentials relies on a number of different K+ channels. The exact composition of K+ channels varies between atria and ventricles and thus is a prerequisite for the observed morphologic differences between atrial and ventricular action potentials. There is interest from a pathophysiologic perspective in identifying atrial selective K+ channels. The rationale for this interest is the possibility of using atrial selective inhibition of K+ channels for treating atrial fibrillation in a manner that avoids ventricular adverse effects. With these considerations in mind, substantial efforts have been devoted toward identifying atrial selective K+ channels. For years the focus was on IKur current conducted by Kv1.5 channels and IKACh current conducted by Kir3.1/Kir3.4 channels. A newcomer to this field is a Ca2+-activated K+ channel with small conductance, known as the SK channel. Historically, the first evidence of cardiac SK channels reported in 1972 did not prompt additional investigations. These studies took advantage of the finding that the peptide toxin apamin could be isolated from bee venom. Apamin demonstrated ex vivo and in vivo effects in dogs and monkeys. Increased heart rate and force of contraction were observed with no obvious ECG effects or impact on blood pressure. Furthermore, apamin clearly was antiarrhythmic. 1 Vick JA, Hassett CC, Shipman WH (1972). Beta Adrenergic and Antiarrhythmic Effect of Apamin, A Component of Bee Venom. Edgewood Arsenal Technical Report EATR 4664:1–13 Google Scholar Sporadic evidence of cardiac Ca2+-activated K+ channels and of rejection of their presence also was reported. 2 Eisner D.A. Vaughan-Jones R.D. Do calcium-activated potassium channels exist in the heart?. Cell Calcium. 1983; 4: 371-386 Crossref PubMed Scopus (25) Google Scholar Apamin later was demonstrated to be a selective target for SK channels, but evidence of cardiac SK channels was not reported until almost 30 years later. 3 Wang W. Watanabe M. Nakamura T. Kudo Y. Ochi R. Properties and expression of Ca2+-activated K+ channels in H9c2 cells derived from rat ventricle. Am J Physiol. 1999; 276: H1559-H1566 PubMed Google Scholar In 2003, evidence of human cardiac SK channels in addition to atrial selective expression with application of surprisingly low concentrations of apamin (50 pM) were reported. 4 Xu Y. Tuteja D. Zhang Z. Xu D. Zhang Y. Rodriguez J. et al. Molecular identification and functional roles of a Ca(2+)-activated K+ channel in human and mouse hearts. J Biol Chem. 2003; 278: 49085-49094 Crossref PubMed Scopus (213) Google Scholar An atrial selective distribution had been suggested by other groups, but there also was abundant evidence, at least from an expression profile, that SK channels also were present in ventricles. 5 Tuteja D. Xu D. Timofeyev V. Lu L. Sharma D. Zhang Z. et al. Differential expression of small-conductance Ca2+-activated K+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes. Am J Physiol Heart Circ Physiol. 2005; 289: H2714-H2723 Crossref PubMed Scopus (178) Google Scholar , 6 Chua S.-K. Chang P.-C. Maruyama M. Turker I. Shinohara T. Shen M.J. et al. Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles. Circ Res. 2011; 108: 971-979 Crossref PubMed Scopus (127) Google Scholar From a functional perspective, there is an apparent atrial selective dominance of SK channel function. Whether this functional selectivity is a consequence of different Ca2+ handling and homeostasis between atria and ventricles is still an open question. Selective activation of heteromeric SK channels contributes to action potential repolarization in mouse atrial myocytesHeart RhythmVol. 12Issue 5PreviewActivation of small conductance calcium-activated potassium (SK) channels is proposed to contribute to repolarization of the action potential in atrial myocytes. This role is controversial, as these cardiac SK channels appear to exhibit an uncharacteristic pharmacology. Full-Text PDF