Protein kinase C regulates functional coupling of beta1-adrenergic receptors to Gi/o-mediated responses in cardiac myocytes.
The effect of protein kinase C (PKC) activation on beta1-adrenergic receptor (beta1-AR) regulation of the cardiac L-type Ca2+ current (ICa,L) was studied using the whole-cell patch clamp technique. Treatment of guinea pig ventricular myocytes with phorbol-12,13-dibutyrate (PDBu) caused a significant decrease in ICa,L sensitivity to stimulation by submaximal beta1-AR activation using isoproterenol (Iso). This decrease in sensitivity was also associated with the ability of higher concentrations of Iso to directly inhibit the stimulatory response. PDBu treatment produced similar effects on H2 histamine receptor-mediated ICa,L responses. In the presence of PDBu, higher concentrations of Iso inhibited the histamine stimulated ICa,L, and this effect was blocked by a selective beta1-AR antagonist. Higher concentrations of histamine also inhibited the Iso stimulated ICa,L, and this effect was blocked by a selective H2 receptor antagonist. The effects of PDBu were blocked by the PKC inhibitor bisindolylmaleimide I, and they were not mimicked by the inactive phorbol ester 4alpha-phorbol-12,13-didecanoate. The inhibitory effects of Iso and histamine were significantly reduced when Gi/o mediated responses were blocked with pertussis toxin. These results suggest that PKC promotes coupling of cardiac beta1-adrenergic and H2 histamine receptors to Gi/o mediated inhibitory responses.
Belevych
Andriy E
AE
Department of Physiology and Biophysics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106-4970, USA.
Juranek
Ivo
I
Harvey
Robert D
RD
D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D004553:Electric Conductivity; D004789:Enzyme Activation / Q000187:drug effects; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*
D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D020746:Calcium Channels, L-Type; D007211:Indoles; D008301:Maleimides; D018342:Receptors, Adrenergic, beta-1; D015240:Phorbol 12,13-Dibutyrate; D006632:Histamine; D037342:Pertussis Toxin; D011493:Protein Kinase C; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; C070515:bisindolylmaleimide I; D002118:Calcium