Novel Mechanism of HERG Current Suppression in LQT2

Shift in Voltage Dependence of HERG Inactivation

From the Department of Cardiovascular Disease (T.N., M.H.) and Autonomic Physiology (T.F., Y.K.), Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; the Laboratory of Molecular Medicine (T.T., Y.N.), Institute of Medical Science, University of Tokyo, Tokyo, Japan; and the Second Department of Internal Medicine (T.N., R.N.), Gunma University School of Medicine, Gunma, Japan.

Correspondence to Masayasu Hiraoka, MD, PhD, Department of Cardiovascular Disease, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo-113, Japan. E-mail hiraoka.card{at}mri.tmd.ac.jp

Abstract—In a Xenopus oocyte heterologous expression system, we characterized the electrophysiology of 3 novel missense mutations of HERG identified in Japanese LQT2 families: T474I (within the S2-S3 linker), A614V, and V630L (in the outer mouth of pore-forming region). For each of the 3 mutations, injection of mutant cRNA alone did not express detectable currents. Coinjection of wild-type (WT) along with each mutant cRNA (T474I/WT, A614V/WT, and V630L/WT) suppressed HERG current in a dominant-negative manner, and the order of magnitude of current suppression was V630L/WT>A614V/WT>T474I/WT. In addition to decreases in slope conductance for all 3 mutants, the voltage dependence of steady-state inactivation was shifted to negative potentials for V630L/WT and A614V/WT. Consequently, channel availability at positive potentials was diminished, and inward rectification was enhanced for these 2 mutants. Thus, missense mutations of HERG caused dominant-negative suppression through multiple mechanisms. The shift in voltage dependence of HERG inactivation and the resulting enhanced inward rectification in A614V/WT and V630L/WT provide a novel mechanism for suppression of the HERG current carrying outward current during the repolarization phase of the action potential.

Key Words: long-QT syndrome • HERG mutation • cardiac arrhythmia

This article has been cited by other articles:

				Q. Gong, C. L. Anderson, C. T. January, and Z. Zhou Pharmacological rescue of trafficking defective HERG channels formed by coassembly of wild-type and long QT mutant N470D subunits Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H652 - H658. [Abstract] [Full Text] [PDF]

				K. J Paavonen, H. Chapman, P. J Laitinen, H. Fodstad, K. Piippo, H. Swan, L. Toivonen, M. Viitasalo, K. Kontula, and M. Pasternack Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2 (HERG) Cardiovasc Res, September 1, 2003; 59(3): 603 - 611. [Abstract] [Full Text] [PDF]

				G. Q. Teng, J. P Lees-Miller, Y. Duan, B.-T. Li, P. Li, and H. J Duff [K+]o-dependent change in conformation of the HERG1 long QT mutation N629D channel results in partial reversal of the in vitro disease phenotype Cardiovasc Res, March 1, 2003; 57(3): 642 - 650. [Abstract] [Full Text] [PDF]

				F. S. Cayabyab, F. W. L. Tsui, and L. C. Schlichter Modulation of the ERG K+ Current by the Tyrosine Phosphatase, SHP-1 J. Biol. Chem., December 6, 2002; 277(50): 48130 - 48138. [Abstract] [Full Text] [PDF]

				K. Hayashi, M. Shimizu, H. Ino, M. Yamaguchi, H. Mabuchi, N. Hoshi, and H. Higashida Characterization of a novel missense mutation E637K in the pore-S6 loop of HERG in a patient with long QT syndrome Cardiovasc Res, April 1, 2002; 54(1): 67 - 76. [Abstract] [Full Text] [PDF]

				F.-D. Huang, J. Chen, M. Lin, M. T. Keating, and M. C. Sanguinetti Long-QT Syndrome-Associated Missense Mutations in the Pore Helix of the HERG Potassium Channel Circulation, August 28, 2001; 104(9): 1071 - 1075. [Abstract] [Full Text] [PDF]

				C. E. Clancy and Y. Rudy Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death Cardiovasc Res, May 1, 2001; 50(2): 301 - 313. [Abstract] [Full Text] [PDF]

				C.-C. Shieh, M. Coghlan, J. P. Sullivan, and M. Gopalakrishnan Potassium Channels: Molecular Defects, Diseases, and Therapeutic Opportunities Pharmacol. Rev., December 1, 2000; 52(4): 557 - 594. [Abstract] [Full Text] [PDF]

				C.-E. Chiang and D. M. Roden The long QT syndromes: genetic basis and clinical implications J. Am. Coll. Cardiol., July 1, 2000; 36(1): 1 - 12. [Abstract] [Full Text] [PDF]

				G. A. Robertson LQT2 : Amplitude Reduction and Loss of Selectivity in the Tail That Wags the HERG Channel Circ. Res., March 17, 2000; 86(5): 492 - 493. [Full Text] [PDF]

				J. P. Lees-Miller, Y. Duan, G. Q. Teng, K. Thorstad, and H. J. Duff Novel Gain-of-Function Mechanism in K+ Channel-Related Long-QT Syndrome: : Altered Gating and Selectivity in the HERG1 N629D Mutant Circ. Res., March 17, 2000; 86(5): 507 - 513. [Abstract] [Full Text] [PDF]

				G. A. Gintant Characterization and functional consequences of delayed rectifier current transient in ventricular repolarization Am J Physiol Heart Circ Physiol, March 1, 2000; 278(3): H806 - H817. [Abstract] [Full Text] [PDF]

				R. Fleischhauer, M. W. Davis, I. Dzhura, A. Neely, L. Avery, and R. H. Joho Ultrafast Inactivation Causes Inward Rectification in a Voltage-Gated K+ Channel from Caenorhabditis elegans J. Neurosci., January 15, 2000; 20(2): 511 - 520. [Abstract] [Full Text] [PDF]

				D. M Roden and J. R Balser A plethora of mechanisms in the HERG-related long QT syndrome: Genetics meets electrophysiology Cardiovasc Res, November 1, 1999; 44(2): 242 - 246. [Full Text] [PDF]

				T. Nakajima, T. Furukawa, Y. Hirano, T. Tanaka, H. Sakurada, T. Takahashi, R. Nagai, T. Itoh, Y. Katayama, Y. Nakamura, et al. Voltage-shift of the current activation in HERG S4 mutation (R534C) in LQT2 Cardiovasc Res, November 1, 1999; 44(2): 283 - 293. [Abstract] [Full Text] [PDF]

				F. Lehmann-Horn and K. Jurkat-Rott Voltage-Gated Ion Channels and Hereditary Disease Physiol Rev, October 1, 1999; 79(4): 1317 - 1372. [Abstract] [Full Text] [PDF]

				M. Furutani, M. C. Trudeau, N. Hagiwara, A. Seki, Q. Gong, Z. Zhou, S.-i. Imamura, H. Nagashima, H. Kasanuki, A. Takao, et al. Novel Mechanism Associated With an Inherited Cardiac Arrhythmia : Defective Protein Trafficking by the Mutant HERG (G601S) Potassium Channel Circulation, May 4, 1999; 99(17): 2290 - 2294. [Abstract] [Full Text] [PDF]

				J. Chen, A. Zou, I. Splawski, M. T. Keating, and M. C. Sanguinetti Long QT Syndrome-associated Mutations in the Per-Arnt-Sim (PAS) Domain of HERG Potassium Channels Accelerate Channel Deactivation J. Biol. Chem., April 9, 1999; 274(15): 10113 - 10118. [Abstract] [Full Text] [PDF]

				A. J. Moss, W. Zareba, E. S. Kaufman, E. Gartman, D. R. Peterson, J. Benhorin, J. A. Towbin, M. T. Keating, S. G. Priori, P. J. Schwartz, et al. Increased Risk of Arrhythmic Events in Long-QT Syndrome With Mutations in the Pore Region of the Human Ether-a-go-go-Related Gene Potassium Channel Circulation, February 19, 2002; 105(7): 794 - 799. [Abstract] [Full Text] [PDF]