Two components of delayed rectifier K+ current in heart: molecular basis, functional diversity, and contribution to repolarization.
Delayed rectifier K+ current (IK) is the major outward current responsible for ventricular repolarization. Two components of IK (IKr and IKs) have been identified in many mammalian species including humans. IKr plays a pivotal role in normal ventricular repolarization. A prolongation of action potential duration (APD) under a variety of conditions would favor the activation of IKs so that to prevent excessive repolarization delay causing early afterdepolarization. The pore-forming a subunits of IKr and IKs are composed of HERG (KCNH2) and KvLQT1 (KCNQ1), respectively. KvLQT1 is associated with a function-altering beta subunit, minK to form IKs. HERG may be associated with mink (KCNE1) and/or minK-related protein (MiRP1) to form IKr, but the issue remains to be established. IKs is enhanced, whereas IKr is usually attenuated by beta-adrenergic stimulation via cyclic adenosine 3',5'-monophosphate (cAMP)/protein kinase A-dependent pathways. There exist regional differences in the density of IKr and IKs transmurally (endo-epicardial) and along the apico-basal axis, contributing to the spatial heterogeneity of ventricular repolarization. A decrease of IKr or IKs by mutations in either HERG, KvLQT1, or KCNE family results in inherited long QT syndrome (LQTS) with high risk for Torsades de pointes (TdP)-type polymorphic ventricular tachycardia and ventricular fibrillation. As to the pharmacological treatment and prevention of ventricular tachyarrhythmias, selectively block of IKs is expected to be more beneficial than selectively block of IKr in terms of homogeneous prolongation of refractoriness at high heart rates especially in diseased hearts including myocardial ischemia.
Cheng
Jian-hua
JH
Department of Pharmacology, Faculty of Basic Medical Sciences, School of Medicine, Tongji University, Shanghai 200331, China. dewang@online.sh.cn
Kodama
Itsuo
I
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013045:Species Specificity
D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011943:Receptors, Adrenergic, beta; C059983:potassium channel protein I(sk)