Receptor phosphorylation does not mediate cross talk between muscarinic M(3) and bradykinin B(2) receptors.
This study examined cross talk between phospholipase C-coupled muscarinic M(3) and bradykinin B(2) receptors coexpressed in Chinese hamster ovary (CHO) cells. Agonists of either receptor enhanced phosphoinositide signaling (which rapidly desensitized) and caused protein kinase C (PKC)-independent, homologous receptor phosphorylation. Muscarinic M(3) but not bradykinin B(2) receptors were also phosphorylated after phorbol ester activation of PKC. Consistent with this, muscarinic M(3) receptors were phosphorylated in a PKC-dependent fashion after bradykinin B(2) receptor activation, but muscarinic M(3) receptor activation did not influence bradykinin B(2) receptor phosphorylation. Despite heterologous phosphorylation of muscarinic M(3) receptors, phosphoinositide and Ca(2+) signaling were unaffected. In contrast, marked heterologous desensitization of bradykinin-mediated responses occurred despite no receptor phosphorylation. This desensitization was associated with a sustained component of muscarinic receptor-mediated signaling, whereas bradykinin's inability to influence muscarinic receptor-mediated responses was associated with rapid and full desensitization of bradykinin responses. Thus the mechanism of functional cross talk most likely involves depletion of a shared signaling component. These data demonstrate that receptor phosphorylation is not a prerequisite for heterologous desensitization and that such desensitization is not obligatory after heterologous receptor phosphorylation.
Willars
G B
GB
Department of Cell Physiology, University of Leicester, Leicester, United Kingdom.
Müller-Esterl
W
W
Nahorski
S R
SR
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D016466:CHO Cells / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007294:Inositol / Q000493:pharmacokinetics; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D016210:Methacholine Chloride / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010766:Phosphorylation; D020239:Receptor Cross-Talk / Q000502:physiology*; D043782:Receptor, Bradykinin B2; D043587:Receptor, Muscarinic M3; D018002:Receptors, Bradykinin / Q000235:genetics / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014316:Tritium; D010738:Type C Phospholipases / Q000378:metabolism
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043782:Receptor, Bradykinin B2; D043587:Receptor, Muscarinic M3; D018002:Receptors, Bradykinin; D011976:Receptors, Muscarinic; D011994:Recombinant Proteins; D016210:Methacholine Chloride; D014316:Tritium; D007294:Inositol; D001285:Atropine; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D001920:Bradykinin; D002118:Calcium