art Tseng 2001

J Mol Cell Cardiol 33, 835–849 (2001) doi:10.1006/jmcc.2000.1317, available online at http://www.idealibrary.com on Basic Cardiac Electrophysiology I Kr : The hERG Channel Gea-Ny Tseng Department of Physiology, Virginia Commonwealth University, Richmond, VA 23298, USA (Received 29 November 2000, accepted 6 December 2000, published electronically 24 January 2001) G.-N. T . I Kr : The hERG Channel. Journal of Molecular and Cellular Cardiology (2001) 33, 835–849. The rapid delayed rectifier (I Kr ) channel is important for cardiac action potential repolarization. Suppressing I Kr function, due to either genetic defects in its pore-forming subunit (hERG) or adverse drug effects, can lead to long-QT (LQT ) syndr ome that carries incre ased risk of life -thre aten ing arrhy thmia s. The impl icati on of I Kr in cardi ac arrhythmias and in anti-arrhythmic/pro-arrhythmic actions of drugs has driven intensive research interests in its struct ure–f uncti on relat ionsh ip, the linkage between LQT -assoc iated mutation s and chan ges in channel function, and the mechanism of drug actions. This review will cover the following topics: (1) heterogeneous contribution of I Kr to action potential repolarization in the heart, (2) structure–function relationship of I Kr /hERG channels, (3) role of regulatory subunits in I Kr /hERG channel function, (4) structural basis for the unique pharmacological properties of I Kr /hERG channels, and (5) I Kr /hERG channel modulation by changes in cellular milieu under physiological and pathological conditions of the heart. It is anticipated that further advances in our understanding of I Kr /hERG, particularly in the areas of roles of different ( and ) subunits in native I Kr function, alterations in I Kr function in diseased hearts, and the 3-dimensional structure of the I Kr /hERG pore based on homology modeling using the KcsA model, will help us better define the role of I Kr in arrhythmias and design therapeutic agents that can increase I Kr and are useful for LQT syndrome. 2001 Academic Press K W: I Kr , Human ether-a-go-go related gene, Long-QT syndrome, Class III anti-arrhythmic drugs. the molecular basis of I Kr channel function in the Introduction heart, 8 the biophys ical prop ert ies of I Kr /hERG gati ng, 9 LQT -associ ated mutations in hERG, 10,11 and the The rapid component of delayed rectifier (I Kr ) con- tributes to phase 3 repolari zation in cardiac acti on mechanisms for congenital and acquired LQT syndrome. 12,13 potentials. 1,2 Genetic defec ts in the major pore-f orm- ing subu nit (hER G) 3 or in theputati ve regulatory ( ) Th is mi ni re vi ew wi ll be gin wi th a di s cu ss io n of the heterogeneous contribution of I Kr to action subunit (MiRP1) 4 of I Kr channe ls are associ ated with congenital ( LQT2 and LQT6) and acquired long-QT pot enti al repol arization in the heart. This topic bear s fun dame ntal importa nce in the attempt to syndrome, 5 that carries increased risk of life-threat- eni ng car diacarrhyt hmi as. I Kr is the target of a group understan d the li nkage betwe en defects in I Kr channel functi on (eit her geneti c or acquired) and of potent and spec ific class III anti -arr hyth micdrugs, methanesulfonanilides. 6,7 It can also be blocked by a arrh ythmogen esi s. This is fol lowe d by a summary of current knowledge about the structure-function wide range of pharmacolog ical agen ts with dif fer ent chemical structures. The implicatio n of I Kr in card ia c re lat io ns hi p of I Kr /hERG channels . The emphasis of this discussion is on aspects that are relevant for arrhythmias and in anti-arrhythmic or pro-arrhythmic actions of drugs highli ghts the importance of unders tand ing struc tur al determinants of I Kr contribution to action potential repolarization, and of underst andi ng it s role in action pot enti al repol arizati on,itsstru ct ure–functi onrelations hi p,and I Kr blockade by drugs. The two following sections are about new concepts that have emerged since the mechanism of drug actions on I Kr . Tremendous insi ghtsinto the seissues have bee n generated by the pre vious revi ews (‘ ‘Rol e of re gul atory subunits in I Kr /hERG channe l funct ion’ ’, ‘ ‘struc tural basis for intensive research efforts during the past few years. The se haveled to exc ellentrec ent reviews discus sin g the unique phar macological prop erties of I Kr /hERG Please address all corres ponden ce to: Gea-Ny Ts eng, PhD, Depar tment of Patho logy , Vi rgin ia Commonweal th Unive rsity , 1101 E. Marshall Street, Richmond, VA 23298, USA; Phone: 804-827-0811; Fax: 804-828-7382; E-mail: [email protected] 0022–2828/01/050835+15 $35.00/0 2001 Academic Press

art Tseng 2001

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