RT Journal Article SR Electronic T1 Cross Talk Between m3-Muscarinic and β2-Adrenergic Receptors at the Level of Receptor Phosphorylation and Desensitization JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 813 OP 823 VO 56 IS 4 A1 David C. Budd A1 R. A. John Challiss A1 Kenneth W. Young A1 Andrew B. Tobin YR 1999 UL http://molpharm.aspetjournals.org/content/56/4/813.abstract AB In this study we investigated cross talk between m3-muscarinic and β2-adrenergic receptors coexpressed in Chinese hamster ovary (CHO-m3/β2) cells, focusing on two possible mechanisms of regulation. The first mechanism is based on recent in vitro studies demonstrating that G protein-coupled receptor kinase (GRK) activity, the protein kinase responsible for β2-adrenergic receptor homologous phosphorylation and desensitization, may be regulated by calcium/calmodulin and membrane phosphatidylinositol 4,5-bisphosphate. Stimulation of the phospholipase C signaling pathway via m3-muscarinic receptors in CHO-m3/β2 cells increased intracellular free calcium by ∼10 fold and membrane phosphatidylinositol 4,5-bisphosphate levels decreased by ∼74%. However, despite these changes the ability of endogenous kinases, possibly the GRKs, to phosphorylate the β2-adrenergic receptor was not altered. The second mechanism investigated involves a direct heterologous phosphorylation of the β2-adrenergic receptor after muscarinic receptor stimulation. Activation of m3-muscarinic receptors did mediate heterologous phosphorylation of β2-adrenergic receptors in a GRK-independent fashion, via protein kinase C. Heterologous β2-adrenergic receptor phosphorylation correlated with receptor desensitization as measured by a loss in guanine-nucleotide sensitive-high affinity agonist binding and reduction in maximal cAMP response. This receptor cross talk may have a profound physiological importance in a wide variety of cell types, for example smooth muscle, where these two receptors are known to be coexpressed. The American Society for Pharmacology and Experimental Therapeutics