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Protein kinase C regulates functional coupling of β1‐adrenergic receptors to Gi/o‐mediated responses in cardiac myocytes
Author(s) -
Belevych Andriy E.,
Juranek Ivo,
Harvey Robert D.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0647fje
Subject(s) - protein kinase c , pertussis toxin , bisindolylmaleimide , histamine , medicine , endocrinology , phorbol , receptor , receptor antagonist , chemistry , antagonist , pharmacology , g protein , biology , signal transduction , biochemistry
The effect of protein kinase C (PKC) activation on β 1 ‐adrenergic receptor (β 1 ‐AR) regulation of the cardiac L‐type Ca 2+ 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 I Ca,L sensitivity to stimulation by submaximal β 1 ‐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 β 1 ‐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 4a‐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 β 1 ‐adrenergic and H 2 histamine receptors to Gi/o mediated inhibitory responses.