Differential nature of cross-talk among three 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 this work, we show that exposure of adult rat cardiomyocytes to isoproterenol (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 M2-muscarinic receptor (MR) agonist, carbachol (Cch), and a decreased inhibition of AC by A1-adenosine receptor (AdR) agonist, N6-phenylisopropyladenosine (R-PIA). Chronic exposure of cells to Cch caused the desensitization of M2-MR-coupled AC, decreased the inhibitory action of R-PIA on AC and increased ISO-stimulated AC, while chronic exposure to R-PIA caused the desensitization of A1-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.