Phosphorylation-independent regulation of cardiac IK by guanine nucleotides and isoproterenol.
We tested for direct G protein regulation of delayed rectifier K+ (IK) channels, by measuring IK currents in guinea pig ventricular cells using patch-clamp procedures. In excised inside-out patches, IK was enhanced by adding guanosine triphosphate or guanosine 5'-O-(3-thiotriphosphate) to the cytoplasmic side, even in the presence of phosphorylation inhibitors. Enhancement of patch IK did not require extracellular agonist; however, enhancement of IK was also seen when isoproterenol was included in the pipette solution. Whole cell IK currents were increased by isoproterenol when phosphorylation pathways were blocked. These data demonstrate that guanine nucleotides and beta-adrenergic agonists can enhance IK by a phosphorylation-independent pathway. Our findings are consistent with a direct coupling of the beta-adrenergic receptor to the cardiac IK channel via a membrane-delimited G protein pathway, in addition to the well-established indirect pathway.
Freeman
L C
LC
Department of Physiology, School of Medicine and Dentistry, University of Rochester, New York 14642.
Kwok
W M
WM
Kass
R S
RS
D000818:Animals; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004594:Electrophysiology; D006150:Guanine Nucleotides / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D013873:Thionucleotides / Q000494:pharmacology
D006150:Guanine Nucleotides; D015221:Potassium Channels; D013873:Thionucleotides; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D006160:Guanosine Triphosphate; D000242:Cyclic AMP; D007545:Isoproterenol