DIFFERENTIAL NATURE OF CROSS-TALK AMONG 3 G-COUPLED RECEPTORS REGULATING ADENYLYL-CYCLASE IN RAT CARDIOMYOCYTES CHRONICALLY EXPOSED TO RECEPTOR AGONISTS

Chronic exposure of cells to cognate agonists has been established to cause homologous desensitization of G protein-coupled receptors. In th is work, we show that exposure of adult rat cardiomyocytes to isoprote renol (ISO) for 24 h led to the desensitization of beta-adrenoceptor ( beta-AR) coupled adenylyl cyclase (AC) activity, which was associated with an increased inhibition of AC by M-2-muscarinic receptor (MR) ago nist, carbachol (Cch), and a decreased inhibition of AC by A(1)-adenos ine receptor (AdR) agonist, N6-phenylisopropyladenosine (R-PIA). Chron ic exposure of cells to Cch caused the desensitization of M-2-MR-coupl ed AC, decreased the inhibitory action of R-PIA on AC and increased IS O-stimulated AC, while chronic exposure to R-PIA caused the desensitiz ation of A(1)-AdR-coupled AC and modestly increased ISO-stimulated AC without any significant effect on Cch inhibition of the enzyme. Thus, chronic exposure of cardiomyocytes revealed for the first time a more complex and differential nature of cross-talk among the three major G- coupled receptors in modulating AC.