Functional Knockout of the Transient Outward Current, Long-QT Syndrome, and Cardiac Remodeling in Mice Expressing a Dominant-Negative Kv4 Subunit

From the Departments of Molecular Biology and Pharmacology (D.M.B., H.X., J.M.N.) and Surgery (R.B.S.), Washington University Medical School, St Louis, Mo.

Correspondence to Dr Jeanne M. Nerbonne, Department of Molecular Biology and Pharmacology, Washington University Medical School, 660 South Euclid Ave, St Louis, MO 63110. E-mail jnerbonn{at}pharmdec.wustl.edu

Abstract—A novel in vivo experimental strategy, involving cell type–specific expression of a dominant-negative K⁺ channel pore-forming subunit, was developed and exploited to probe the molecular identity of the cardiac transient outward K⁺ current (I_to). A point mutation (W to F) was introduced at position 362 in the pore region of Kv4.2 to produce a nonconducting mutant (Kv4.2W362F) subunit. Coexpression of Kv4.2W362F with Kv4.2 (or Kv4.3) attenuates the wild-type currents, and the effect is subfamily specific; ie, Kv4.2W362F does not affect heterologously expressed Kv1.4 currents. With the use of the -myosin heavy chain promoter to direct cardiac-specific expression, several lines of Kv4.2W362F transgenic mice were generated. Electrophysiological recordings reveal that I_to is selectively eliminated in ventricular myocytes isolated from transgenic mice expressing Kv4.2W362F, thereby demonstrating directly that the Kv 4 subfamily underlies I_to in the mammalian heart. Functional knockout of I_to leads to marked increases in action potential durations in ventricular myocytes and to prolongation of the QT interval in surface ECG recordings. In addition, a novel rapidly activating and inactivating K⁺ current, which is not detectable in myocytes from nontransgenic littermates, is evident in Kv4.2W362F-expressing ventricular cells. Importantly, these results demonstrate that electrical remodeling occurs in the heart when the expression of endogenous K⁺ channels is altered.

Key Words: transgenic mouse • transient outward current • ventricle • action potential • long QT

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				J. L. Greenstein, R. Wu, S. Po, G. F. Tomaselli, and R. L. Winslow Role of the Calcium-Independent Transient Outward Current Ito1 in Shaping Action Potential Morphology and Duration Circ. Res., November 24, 2000; 87(11): 1026 - 1033. [Abstract] [Full Text] [PDF]

				S. P. Thomas, L. Bircher-Lehmann, S. A. Thomas, J. Zhuang, J. E. Saffitz, and A. G. Kleber Synthetic Strands of Neonatal Mouse Cardiac Myocytes : Structural and Electrophysiological Properties Circ. Res., September 15, 2000; 87(6): 467 - 473. [Abstract] [Full Text] [PDF]

				A. W. Varga, A. E. Anderson, J. P. Adams, H. Vogel, and J. D. Sweatt Input-Specific Immunolocalization of Differentially Phosphorylated Kv4.2 in the Mouse Brain Learn. Mem., September 1, 2000; 7(5): 321 - 332. [Abstract] [Full Text]

				M. T. Perez-Garcia, J. R. Lopez-Lopez, A. M. Riesco, U. C. Hoppe, E. Marban, C. Gonzalez, and D. C. Johns Viral Gene Transfer of Dominant-Negative Kv4 Construct Suppresses an O2-Sensitive K+ Current in Chemoreceptor Cells J. Neurosci., August 1, 2000; 20(15): 5689 - 5695. [Abstract] [Full Text] [PDF]

				W. Han, Z. Wang, and S. Nattel A comparison of transient outward currents in canine cardiac Purkinje cells and ventricular myocytes Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H466 - H474. [Abstract] [Full Text] [PDF]

				S. A. Malin and J. M. Nerbonne Elimination of the Fast Transient in Superior Cervical Ganglion Neurons with Expression of KV4.2W362F: Molecular Dissection of IA J. Neurosci., July 15, 2000; 20(14): 5191 - 5199. [Abstract] [Full Text] [PDF]

				T W Claydon, M R Boyett, A Sivaprasadarao, K Ishii, J M Owen, H A O'Beirne, R Leach, K Komukai, and C H Orchard Inhibition of the K+ channel Kv1.4 by acidosis: protonation of an extracellular histidine slows the recovery from N-type inactivation J. Physiol., July 15, 2000; 526(2): 253 - 264. [Abstract] [Full Text] [PDF]

				W. Guo, H. Li, B. London, and J. M. Nerbonne Functional Consequences of Elimination of Ito, f and Ito, s : Early Afterdepolarizations, Atrioventricular Block, and Ventricular Arrhythmias in Mice Lacking Kv1.4 and Expressing a Dominant-Negative Kv4 {alpha} Subunit Circ. Res., July 7, 2000; 87(1): 73 - 79. [Abstract] [Full Text] [PDF]

				J. M Nerbonne Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium J. Physiol., June 1, 2000; 525(2): 285 - 298. [Abstract] [Full Text] [PDF]

				B. C Knollmann, B. E C Knollmann-Ritschel, N. J Weissman, L. R Jones, and M. Morad Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin J. Physiol., June 1, 2000; 525(2): 483 - 498. [Abstract] [Full Text] [PDF]

				A. Jeron, G. F. Mitchell, J. Zhou, M. Murata, B. London, P. Buckett, S. D. Wiviott, and G. Koren Inducible polymorphic ventricular tachyarrhythmias in a transgenic mouse model with a long Q-T phenotype Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1891 - H1898. [Abstract] [Full Text] [PDF]

				J. James, A. Sanbe, K. Yager, L. Martin, R. Klevitsky, and J. Robbins Genetic Manipulation of the Rabbit Heart via Transgenesis Circulation, April 11, 2000; 101(14): 1715 - 1721. [Abstract] [Full Text] [PDF]

				L. C. Baker, B. London, B.-R. Choi, G. Koren, and G. Salama Enhanced Dispersion of Repolarization and Refractoriness in Transgenic Mouse Hearts Promotes Reentrant Ventricular Tachycardia Circ. Res., March 3, 2000; 86(4): 396 - 407. [Abstract] [Full Text] [PDF]

				V. S. Chauhan, S. Tuvia, M. Buhusi, V. Bennett, and A. O. Grant Abnormal Cardiac Na+ Channel Properties and QT Heart Rate Adaptation in Neonatal AnkyrinB Knockout Mice Circ. Res., March 3, 2000; 86(4): 441 - 447. [Abstract] [Full Text] [PDF]

				W. H. DuBell, W. J. Lederer, and T. B. Rogers K+ currents responsible for repolarization in mouse ventricle and their modulation by FK-506 and rapamycin Am J Physiol Heart Circ Physiol, March 1, 2000; 278(3): H886 - H897. [Abstract] [Full Text] [PDF]