Regional upregulation of kv2.1-encoded current, I_Kslow2, in Kv1DN mice is abolished by crossbreeding with Kv2DN mice

Overexpression of a truncated Kv1.1 channel transgene in the heart (KvlDN) 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 KvlDN 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 KvlDN mice. Crossbreeding of KvlDN 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 KvlDN mice.