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(Circulation Research. 2005;97:1342.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Targeted Deletion of Kv4.2 Eliminates I_to,f and Results in Electrical and Molecular Remodeling, With No Evidence of Ventricular Hypertrophy or Myocardial Dysfunction

Weinong Guo^*, W. Edward Jung^*, Céline Marionneau^*, Franck Aimond, Haodong Xu, Kathryn A. Yamada, Thomas L. Schwarz, Sophie Demolombe, Jeanne M. Nerbonne

From the Departments of Molecular Biology and Pharmacology (W.G., F.A., H.X., J.M.N.) and Internal Medicine (K.A.Y.), Washington University Medical School, St Louis, Mo; Department of Molecular and Cellular Physiology (W.E.J.), Stanford University Medical School, Palo Alto, Calif; Institut du Thorax (C.M., S.D.), INSERM, Nantes, France; and Program in Neurobiology (T.L.S.), Children’s Hospital, Harvard Medical School, Boston, Mass.

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

Previous studies have demonstrated a role for voltage-gated K⁺ (Kv) channel subunits of the Kv4 subfamily in the generation of rapidly inactivating/recovering cardiac transient outward K⁺ current, I_to,f, channels. Biochemical studies suggest that mouse ventricular I_to,f channels reflect the heteromeric assembly of Kv4.2 and Kv4.3 with the accessory subunits, KChIP2 and Kvß1, and that Kv4.2 is the primary determinant of regional differences in (mouse ventricular) I_to,f densities. Interestingly, the phenotypic consequences of manipulating I_to,f expression in different mouse models are distinct. In the experiments here, the effects of the targeted deletion of Kv4.2 (Kv4.2^–/–) were examined. Unexpectedly, voltage-clamp recordings from Kv4.2^–/– ventricular myocytes revealed that I_to,f is eliminated. In addition, the slow transient outward K⁺ current, I_to,s, and the Kv1.4 protein (which encodes I_to,s) are upregulated in Kv4.2^–/– ventricles. Although Kv4.3 mRNA/protein expression is not measurably affected, KChIP2 expression is markedly reduced in Kv4.2^–/– ventricles. Similar to Kv4.3, expression of Kvß1, as well as Kv1.5 and Kv2.1, is similar in wild-type and Kv4.2^–/– ventricles. In addition, and in marked contrast to previous findings in mice expressing a truncated Kv4.2 transgene, the elimination I_to,f in Kv4.2^–/– mice does not result in ventricular hypertrophy. Taken together, these findings demonstrate not only an essential role for Kv4.2 in the generation of mouse ventricular I_to,f channels but also that the loss of I_to,f per se does not have overt pathophysiological consequences.

Key Words: I_to,s • Kv channels • remodeling • arrhythmia • hypertrophy

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