Functional consequences of elimination of i(to,f) and i(to,s): early afterdepolarizations, atrioventricular block, and ventricular arrhythmias in mice lacking Kv1.4 and expressing a dominant-negative Kv4 alpha subunit.
It was recently reported that the slow transient outward K(+) current, I(to, s), that is evident in mouse left ventricular septal cells is eliminated in mice with a targeted deletion of the Kv1.4 gene (Kv1.4(-/-)). The rapidly inactivating transient outward K(+) current, I(to, f), in contrast, is selectively eliminated in ventricular myocytes isolated from transgenic mice expressing a dominant-negative Kv4 alpha subunit, Kv4.2W362F. Expression of Kv4. 2W362F results in marked prolongation of action potentials and QT intervals. In addition, a slow transient outward K(+) current, that is similar to I(to,s) in wild-type mouse left ventricular septal cells, is evident in all Kv4.2W362F-expressing (left and right) ventricular cells. To test directly the hypothesis that upregulation of Kv1.4 alpha subunit underlies the appearance of this slow transient outward K(+) current in Kv4.2W362F-expressing ventricular cells and to explore the functional consequences of elimination of I(to,f) and I(to,s), mice expressing Kv4.2W362F in the Kv1.4(-/-) background (Kv4.2W362FxKv1.4(-/-)) were generated. Histological and echocardiographic studies revealed no evidence of structural abnormalities or contractile dysfunction in Kv4.2W362FxKv1.4(-/-) mouse hearts. Electrophysiological recordings from the majority (approximately 80%) of cells isolated from the right ventricle and left ventricular apex of Kv4.2W362FxKv1.4(-/-) animals demonstrated that both I(to, f) and I(to,s) are eliminated; action potentials are prolonged significantly; and, in some cells, early afterdepolarizations were observed. In addition, in vivo telemetric ECG recordings from Kv4.2W362FxKv1.4(-/-) animals revealed marked QT prolongation, atrioventricular block, and ventricular tachycardia. These observations demonstrate that upregulation of Kv1.4 contributes to the electrical remodeling evident in the ventricles of Kv4.2W362F-expressing mice and that elimination of both I(to,f) and I(to,s) has dramatic functional consequences.
Guo
W
W
Department of Molecular Biology, Washington University School of Medicine, St. Louis, MO, USA.
Li
H
H
London
B
B
Nerbonne
J M
JM
D000200:Action Potentials; D000818:Animals; D004562:Electrocardiography; D006327:Heart Block / Q000209:etiology*; D051665:Kv1.4 Potassium Channel; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D010641:Phenotype; D015221:Potassium Channels / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D017180:Tachycardia, Ventricular / Q000209:etiology*
C496978:Kcna4 protein, mouse; D051665:Kv1.4 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated