title: Dominant-negative suppression of I(K1) in the mouse heart leads to altered cardiac excitability.
abstract: The inward rectifier potassium current in the heart, I(K1), has been suggested to play a significant role in cardiac excitability by contributing to the late phase of action potential (AP) repolarization and the stabilization of resting potential. To further assess the role of I(K1) in cardiac excitability we have produced transgenic mice expressing a dominant-negative subunit of the Kir2.1 channel, a major molecular determinant of I(K1) in the heart, and studied the effects of I(K1) suppression on major potassium currents, APs and the overall electrical activity of the heart. Kir2.1 channel subunits with a mutated signature sequence (AAA for GYG substitution) were expressed in the heart under control of the alpha-myosin heavy chain promoter. Two lines of transgenic mice were established, both expressing high levels of Kir2.1-AAA-GFP (GFP, green fluorescent protein) subunits in all major parts of the heart. In ventricular myocytes isolated from transgenic mice, I(K1) was reduced by 95% in both lines, leading to a significant prolongation of APs. Surface ECG recordings from anesthetized transgenic mice revealed significant changes in key parameters of excitability, including prolongation of QRS complexes and QT intervals. This study confirms the significant role of I(K1) in control of AP repolarization and major ECG intervals in the intact heart.
authors.affiliation: Department of Physiology, University of Michigan Medical School, Room 7812, Medical Science II 0622, 1150 W Medical Center Drive, Ann Arbor, MI 48109-0622, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: McLerie
authors.forename: Anatoli N
authors.initials: AN
authors.lastname: Lopatin
authors.forename: Anatoli
authors.initials: A
authors.lastname: Lopatin
mesh_terms: D000818:Animals; D004562:Electrocardiography; D005799:Genes, Dominant; D017930:Genes, Reporter; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D011993:Recombinant Fusion Proteins; D011188:Potassium