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.
Hagiwara
Kunie
K
Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Japan.
Nunoki
Kazuo
K
Ishii
Kuniaki
K
Abe
Takaaki
T
Yanagisawa
Teruyuki
T
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D004553:Electric Conductivity; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007700:Kinetics; D051665:Kv1.4 Potassium Channel; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011493:Protein Kinase C / Q000378:metabolism; D051672:Shal Potassium Channels; D014982:Xenopus laevis
D019332:Endothelin-1; D051665:Kv1.4 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases