Molecular Cloning and Functional Expression of the Equine K(+) Channel K(V)11.1 (Ether à Go-Go-Related/KCNH2 Gene) and the Regulatory Subunit KCNE2 from Equine Myocardium

The KCNH2 and KCNE2 genes encode the cardiac voltage-gated K(+) channel K(V)11.1 and its auxiliary β subunit KCNE2. K(V)11.1 is critical for repolarization of the cardiac action potential. In humans, mutations or drug therapy affecting the K(V)11.1 channel are associated with prolongation of the QT intervals on the ECG and increased risk of ventricular tachyarrhythmia and sudden cardiac death—conditions known as congenital or acquired Long QT syndrome (LQTS), respectively. In horses, sudden, unexplained deaths are a well-known problem. We sequenced the cDNA of the KCNH2 and KCNE2 genes using RACE and conventional PCR on mRNA purified from equine myocardial tissue. Equine K(V)11.1 and KCNE2 cDNA had a high homology to human genes (93 and 88%, respectively). Equine and human K(V)11.1 and K(V)11.1/KCNE2 were expressed in Xenopus laevis oocytes and investigated by two-electrode voltage-clamp. Equine K(V)11.1 currents were larger compared to human K(V)11.1, and the voltage dependence of activation was shifted to more negative values with V(1/2) = -14.2±1.1 mV and -17.3±0.7, respectively. The onset of inactivation was slower for equine K(V)11.1 compared to the human homolog. These differences in kinetics may account for the larger amplitude of the equine current. Furthermore, the equine K(V)11.1 channel was susceptible to pharmacological block with terfenadine. The physiological importance of K(V)11.1 was investigated in equine right ventricular wedge preparations. Terfenadine prolonged action potential duration and the effect was most pronounced at slow pacing. In conclusion, these findings indicate that horses could be disposed to both congenital and acquired LQTS.