Role of Ca2+/calmodulin-dependent protein kinase II in the regulation of the cardiac L-type Ca2+ current during endothelin-1 stimulation

Kimiaki Komukai, Jin O-Uchi, Satoshi Morimoto, Makoto Kawai, Kenichi Hongo, Michihiro Yoshimura, Satoshi Kurihara

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16 Scopus citations

Abstract

Endothelin-1 (ET-1) shows a positive inotropic effect on cardiac muscle. Although the L-type Ca2+ current (ICa) is one of the important determinants of cardiac excitation-contraction coupling, the effect of ET-1 on the ICa is not always clear. The controversial results appear to be due to different patch-clamp methods. The present study measured the effect of ET-1 on the ICa of rat ventricular myocytes using the perforated patch-clamp technique. The holding potential was set to -40 mV, and depolarization was applied every 10 s. ET-1 (10 nM) increased the ICa in a monophasic manner. The current reached a steady state 15 min after the application of ET-1, when the measurement was done. Endothelin receptor subtype expression was also investigated using Western immunoblotting. ET A-receptor protein was expressed, but ETB-receptor protein was not expressed, in the cell membranes of rat ventricular myocytes. The effect of ET-1 on the ICa was inhibited by a selective ETA-receptor antagonist, BQ-123, but not by a selective ETB-receptor antagonist, BQ-788. The effect was inhibited by protein kinase C (PKC) inhibitor chelerythrine and Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93, but not by its inactive analog KN-92. The effect of ET-1 was also blocked by another CaMKII inhibitor, autocamtide-2-related inhibitory peptide. These results suggest that ET-1 increases the ICa via the ETA-receptor-PKC-CaMKII pathway.

Original languageEnglish (US)
Pages (from-to)H1902-H1907
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume298
Issue number6
DOIs
StatePublished - Jun 2010
Externally publishedYes

Keywords

  • BQ-123
  • Endothelin A receptor
  • KN-93
  • Perforated patch clamp

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