Published online before print November 17, 2005, doi: 10.1161/01.RES.0000196559.63223.aa
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Submitted on September 8, 2005
Revised on October 19, 2005
Accepted on November 3, 2005
Targeted Deletion of Kv4.2 Eliminates Ito,f and Results in Electrical and Molecular Remodeling, With No Evidence of Ventricular Hypertrophy or Myocardial Dysfunction
Weinong Guo ;
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.
* To whom correspondence should be addressed. 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, Ito,f, channels. Biochemical studies suggest that mouse ventricular Ito,f channels reflect the heteromeric assembly of Kv4.2 and Kv4.3 with the accessory subunits, KChIP2 and Kv
1, and that Kv4.2 is the primary determinant of regional differences in (mouse ventricular) Ito,f densities. Interestingly, the phenotypic consequences of manipulating Ito,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 Ito,f is eliminated. In addition, the slow transient outward K+ current, Ito,s, and the Kv1.4 protein (which encodes Ito,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 Kv1, 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 Ito,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 Ito,f channels but also that the loss of Ito,f per se does not have overt pathophysiological consequences.
Key words: Ito,s • Kv channels • remodeling • arrhythmia • hypertrophy
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