Voltage-gated potassium channels control cardiac repolarization, and mutations of K ؉ channel genes recently have been shown to cause arrhythmias and sudden death in families with the congenital long QT syndrome. The precise mechanism by which the mutations lead to QT prolongation and arrhythmias is uncertain, however. We have shown previously that an N-terminal fragment including the first transmembrane segment of the rat delayed rectifier K ؉ channel Kv1.1 (Kv1.1N206Tag) coassembles with other K ؉ channels of the Kv1 subfamily in vitro, inhibits the currents encoded by Kv1.5 in a dominant-negative manner when coexpressed in Xenopus oocytes, and traps Kv1.5 polypeptide in the endoplasmic reticulum of GH3 cells. Here we report that transgenic mice overexpressing Kv1.1N206Tag in the heart have a prolonged QT interval and ventricular tachycardia. Cardiac myocytes from these mice have action potential prolongation caused by a significant reduction in the density of a rapidly activating, slowly inactivating, 4-aminopyridine sensitive outward K ؉ current. These changes correlate with a marked decrease in the level of Kv1.5 polypeptide. Thus, overexpression of a truncated K ؉ channel in the heart alters native K ؉ channel expression and has profound effects on cardiac excitability.Mutations of the K ϩ channel genes HERG and KVLQT1 cause the autosomal dominant long QT (LQT) syndrome, presumably by interfering with the cardiac currents I Kr and I Ks (1-6). The precise biochemical mechanism by which these mutations cause prolongation of the QT interval is uncertain. A single wild-type potassium channel gene in a heterozygous-affected individual may produce an insufficient number of functional channels to support normal repolarization of the heart. Alternatively, a mutated or truncated channel polypeptide might coassemble with wild-type channel polypeptides to produce nonfunctional channels via a dominant-negative mechanism (7).Voltage-gated potassium channels form multimeric complexes by association of four ␣-subunits (8). We previously have used site-directed mutagenesis and dominant-negative techniques to study structure-function relationships and elucidate the domains that play an important role in Shaker-like potassium channel assembly (9-11). Overexpression of the N-terminal fragment and the first transmembrane segment of the rat brain potassium channel (Kv1.1N206Tag) in Xenopus oocytes inhibited the currents encoded by Kv1.1 and Kv1.5 in a dominant-negative manner. Kv1.1N206Tag also formed in vitro heteromultimeric complexes with Kv1.1 and Kv1.5 (11). Furthermore, we have shown that overexpression of Kv1.1N206Tag in GH3 cells led to the formation of heteromultimeric complexes with the native Kv1.4 and Kv1.5 potassium channel polypeptides (12). These complexes were trapped in the endoplasmic reticulum and did not reach the plasma membrane. The trapping of Kv1.1N206Tag led to its rapid degradation. These experiments elucidated the biochemical mechanisms that underlie the dominant-negative effect of a truncate...

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.