title: Regulation of cardiac inwardly rectifying potassium current IK1 and Kir2.x channels by endothelin-1.
abstract: To elucidate the ionic mechanism of endothelin-1 (ET-1)-induced focal ventricular tachyarrhythmias, the regulation of I(K1) and its main molecular correlates, Kir2.1, Kir2.2 and Kir2.3 channels, by ET-1 was investigated. Native I(K1) in human atrial cardiomyocytes was studied with whole-cell patch clamp. Human endothelin receptors were coexpressed with human Kir2.1, Kir2.2 and Kir2.3 channels in Xenopus oocytes. Currents were measured with a two-microelectrode voltage clamp. In human cardiomyocytes, ET-1 induced a marked inhibition of I(K1) that could be suppressed by the protein kinase C (PKC) inhibitor staurosporine. To investigate the molecular mechanisms underlying this regulation, we studied the coupling of ET(A) receptors to homomeric and heteromeric Kir2.1, Kir2.2 and Kir2.3 channels in the Xenopus oocyte expression system. ET(A) receptors coupled functionally to Kir2.2 and Kir2.3 channels but not to Kir2.1 channels. In Kir2.2 channels lacking functional PKC phosphorylation sites, the inhibitory effect was abolished. The inhibition of Kir2.3 currents could be suppressed by the PKC inhibitors staurosporine and chelerythrine. The coupling of ET(A) receptors to heteromeric Kir2.1/Kir2.2 and Kir2.2/Kir2.3 channels resulted in a strong inhibition of currents comparable with the effect observed in Kir2.2 homomers. Surprisingly, in heteromeric Kir2.1/Kir2.3 channels, no effect was observed. ET-1 inhibits human cardiac I(K1) current via a PKC-mediated phosphorylation of Kir2.2 channel subunits and additional regulatory effects on Kir2.3 channels. This mechanism may contribute to the intrinsic arrhythmogenic potential of ET-1.
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kiesecker
authors.forename: Edgar
authors.initials: E
authors.lastname: Zitron
authors.forename: Daniel
authors.initials: D
authors.lastname: Scherer
authors.forename: Sonja
authors.initials: S
authors.lastname: Lueck
authors.forename: Ramona
authors.initials: R
authors.lastname: Bloehs
authors.forename: Eberhard P
authors.initials: EP
authors.lastname: Scholz
authors.forename: Marcus
authors.initials: M
authors.lastname: Pirot
authors.forename: Sven
authors.initials: S
authors.lastname: Kathöfer
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.forename: Volker A W
authors.initials: VA
authors.lastname: Kreye
authors.forename: Johann
authors.initials: J
authors.lastname: Kiehn
authors.forename: Mathias M
authors.initials: MM
authors.lastname: Borst
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schoels
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Karle
mesh_terms: D000368:Aged; D000470:Alkaloids / Q000378:metabolism; D000818:Animals; D053119:Benzophenanthridines / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000378:metabolism; D006325:Heart Atria / Q000166:cytology; D006801:Humans; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D019311:Staurosporine / Q000378:metabolism; D013610:Tachycardia / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D000470:Alkaloids; D053119:Benzophenanthridines; D019332:Endothelin-1; D004791:Enzyme Inhibitors; C489457:KCNJ2 protein, human; C099489:KCNJ4 protein, human; C489463:Kir2.2 channel; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D044022:Receptor, Endothelin A; C016299:chelerythrine; D011493:Protein Kinase C; D019311:Staurosporine; D011188:Potassium