Regional upregulation of Kv2.1-encoded current, IK,slow2, in Kv1DN mice is abolished by crossbreeding with Kv2DN mice.
Overexpression of a truncated Kv1.1 channel transgene in the heart (Kv1DN) resulted in mice with a prolonged action potential duration due to marked attenuation of a rapidly activating, slowly inactivating potassium current (I(K,slow1)) in ventricular myocytes. Optical mapping and programmed electrical stimulation revealed inducible ventricular tachycardia due to spatial dispersion of repolarization and refractoriness. Here we show that a delayed rectifier with slower inactivation kinetics (I(K,slow2)) was selectively upregulated in Kv1DN cardiocytes. This electrical remodeling was spatially restricted to myocytes derived from the apex of the left ventricle. Biophysical and pharmacological studies of I(K,slow2) indicate that it resembles Kv2-encoded currents. Northern blot analyses and real-time PCR revealed upregulation of Kv2.1 transcript in Kv1DN mice. Crossbreeding of Kv1DN mice with mice expressing a truncated Kv2.1 polypeptide (Kv2DN) eliminated I(K,slow2). In summary, our data indicate that the spatially restrictive upregulation of Kv2.1-encoded currents underlies the increased dispersion of the repolarization observed in Kv1DN mice.
Zhou
Jun
J
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kodirov
Sodikdjon
S
Murata
Mitsunobu
M
Buckett
Peter D
PD
Nerbonne
Jeanne M
JM
Koren
Gideon
G
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D051668:Delayed Rectifier Potassium Channels; D004553:Electric Conductivity; D004594:Electrophysiology; D005260:Female; D006352:Heart Ventricles; D006824:Hybridization, Genetic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D051669:Shab Potassium Channels; D019789:Tetraethylammonium / Q000494:pharmacology; D015854:Up-Regulation; D020257:Ventricular Remodeling
D051668:Delayed Rectifier Potassium Channels; C496990:Kcnb1 protein, mouse; D010446:Peptide Fragments; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051669:Shab Potassium Channels; D019789:Tetraethylammonium; D015761:4-Aminopyridine