Role of the rapid delayed rectifier K+ current in human induced pluripotent stem cells derived cardiomyocytes.

Abstract

The action potential (AP) in cardiac tissue is important for initiating and coordinating contractions in the heart. In addition, the long refractory period minimizes the potential for developing extrasystoles and arrhythmias [1]. The AP is generated by coordinate changes in different ionic currents. In human (or canine) adult ventricular cells, the depolarization phase of the AP is mainly through the influx of Na+ and Ca2+ through specific voltage gated channels [2]. Repolarization of the AP is regulated by activation of a number of different K+ currents which play important roles in regulating the AP. These K+ currents include: (i) a Ca2+-independent transient outward K+ current (Ito), (ii) an inwardly rectifying K+ current (IK1), and (iii) the rapidly and slowly activating delayed rectifier K+ channel currents (IKr and IKs, respectively). Previous studies have demonstrated that there is an excess of several K+ currents necessary for cardiac repolarization such that a net outward current remains available for repolarization if one or more currents are reduced (repolarization reserve) [3– 5]. Therefore, cardiac tissue with a lower repolarization reserve is associated with a prolonged ventricular action potential and an increased incidence of developing arrhythmias [6]. Mutations in KCNH2 (the gene which encodes IKr) cause a decrease in the magnitude of IKr and are associated with Long QT syndrome [7,8]. Patients afflicted with Long QT have episodes of fainting, irregular heartbeats and an increased incidence of developing ventricular arrhythmias. Interestingly, many non-cardiac medications have also been shown to block IKr [9,10] which has resulted in drug companies extensively testing potential therapeutic compounds for IKr block prior to introduction to the market.