This study examined cross talk between phospholipase C-coupled muscarinic M3and bradykinin B2receptors 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 M3but not bradykinin B2receptors were also phosphorylated after phorbol ester activation of PKC. Consistent with this, muscarinic M3receptors were phosphorylated in a PKC-dependent fashion after bradykinin B2receptor activation, but muscarinic M3receptor activation did not influence bradykinin B2receptor phosphorylation. Despite heterologous phosphorylation of muscarinic M3receptors, phosphoinositide and Ca2+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.