Differential inhibition of transient outward currents of Kv1.4 and Kv4.3 by endothelin

The effects of endothelin on the transient outward K⁺ currents were compared between Kv1.4 and Kv4.3 channels in Xenopus oocytes expression system. Both transient outward K⁺ currents were decreased by stimulation of endothelin receptor ET_A coexpressed with the K ⁺ channels. Transient outward current of Kv1.4 was decreased by about 85% after 10^-8 M ET-1, while that of Kv4.3 was decreased by about 60%. By mutagenesis experiments we identified two phosphorylation sites of PKC and CaMKII in Kv1.4 responsible for the decrease in I_to by ET-1. In Kv4.3 a PKC phosphorylation site was identified which is in part responsible for the decrease in I_to. Differences in the suppression of I_to could be ascribed to the difference in intracellular signaling including the number of phosphorylation sites. These findings might give clues for the understanding of molecular mechanism of ventricular arrhythmias in heart failure, in which endothelin is involved in the pathogenesis.