title: Phorbol ester- and diacylglycerol-mediated desensitization of cardiac beta-adrenergic receptors.
abstract: There are specific phorbol ester receptors on cardiac myocytes which may be identical with the calcium/phospholipid-dependent protein kinase (protein kinase C). Incubation of enzymatically dissociated rat cardiac myocytes with biologically active phorbol esters (such as 4 beta-phorbol-12, 13-dibutyrate and 12-O-tetradecanoyl phorbol-13-acetate) leads to a time- and concentration-dependent loss of beta-adrenergic receptors detectable with the hydrophilic ligand [3H]-CGP-12177. This loss is attributable to a reduction in both maximal beta-receptor numbers and their affinities. The synthetic diacylglycerol, 1-oleyl-2-acetyldiglycerol, which is known to activate protein kinase C, also induces desensitization of beta-receptors. Both phorbol dibutyrate and 1-oleyl-2-acetyldiglycerol have additive effects to isoproterenol, suggesting a separate site of action in promoting beta-receptor desensitization. The effects of phorbol dibutyrate and 1-oleyl-2-acetyldiglycerol are prevented by colchicine (but not its inactive analog, trimethylcolchicinic acid), indicating a microtubule dependence. The loss of membrane-bound beta-receptors after phorbol dibutyrate- or 1-oleyl-2-acetyldiglycerol preincubation is accompanied by an increase in beta-receptors associated with a cytosol-derived vesicular fraction devoid of plasma membrane markers, a finding consistent with an internalization process. These results suggest that protein kinase C activation by diacylglycerols derived from receptor-linked phosphoinositide hydrolysis may be a novel mechanism of cardiac beta-receptor desensitization.
authors.forename: C J
authors.initials: CJ
authors.lastname: Limas
authors.forename: C
authors.initials: C
authors.lastname: Limas
mesh_terms: D000818:Animals; D003078:Colchicine / Q000494:pharmacology; D004075:Diglycerides / Q000494:pharmacology*; D005989:Glycerides / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology*; D010704:Phorbols / Q000494:pharmacology*; D011493:Protein Kinase C; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
chemical_list: D004075:Diglycerides; D005989:Glycerides; D010703:Phorbol Esters; D010704:Phorbols; D011943:Receptors, Adrenergic, beta; D011494:Protein Kinases; D011493:Protein Kinase C; D007545:Isoproterenol; D003078:Colchicine