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Molecular Pharmacology

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Research ArticleArticle

Cross Talk Between m3-Muscarinic and β2-Adrenergic Receptors at the Level of Receptor Phosphorylation and Desensitization

David C. Budd, R. A. John Challiss, Kenneth W. Young and Andrew B. Tobin
Molecular Pharmacology October 1999, 56 (4) 813-823;
David C. Budd
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R. A. John Challiss
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Kenneth W. Young
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Andrew B. Tobin
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Abstract

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.

Footnotes

  • Send reprint requests to: Dr. Andrew B. Tobin, Department of Cell Physiology and Pharmacology, University of Leicester, P.O. Box 138, Medical Sciences Building, University Road, Leicester, LE1 9HN, United Kingdom. E-mail: TBA{at}le.ac.uk

  • This work was supported by Wellcome Trust Grants 047600/96 and 16895/96.

  • Abbreviations:
    CHO
    Chinese hamster ovary
    G protein-coupled receptor kinase
    Ins(1,4,5)P3, inositol 1,4,5-trisphosphate
    PIP2
    phosphatidylinositol 4,5-bisphosphate
    PKA
    protein kinase A
    PKA amide inhibitor
    myristoylated protein kinase A inhibitor (14–22) amide (N-Myr-Gly-Arg-Thr-Gly-Arg-Arg-Asn-Ala-Ile-NH2)
    PKC
    protein kinase C
    PLC
    phosphoinositide-specific phospholipase C
    • Received February 15, 1999.
    • Accepted July 8, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (4)
Molecular Pharmacology
Vol. 56, Issue 4
1 Oct 1999
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Research ArticleArticle

Cross Talk Between m3-Muscarinic and β2-Adrenergic Receptors at the Level of Receptor Phosphorylation and Desensitization

David C. Budd, R. A. John Challiss, Kenneth W. Young and Andrew B. Tobin
Molecular Pharmacology October 1, 1999, 56 (4) 813-823;

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Research ArticleArticle

Cross Talk Between m3-Muscarinic and β2-Adrenergic Receptors at the Level of Receptor Phosphorylation and Desensitization

David C. Budd, R. A. John Challiss, Kenneth W. Young and Andrew B. Tobin
Molecular Pharmacology October 1, 1999, 56 (4) 813-823;
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