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 (whi ch rapidly desensitized) and caused protein kinase C (PKC)-independent, hom ologous receptor phosphorylation. Muscarinic Mg but not bradykinin Bz recep tors were also phosphorylated after phorbol ester activation of PKC. Consis tent with this, muscarinic M-3 receptors were phosphorylated in a PKC-depen dent fashion after bradykinin Ba receptor activation, but muscarinic M-3 re ceptor activation did not influence bradykinin B-2 receptor phosphorylation . Despite heterologous phosphorylation of muscarinic M-3 receptors, phospho inositide and Ca2+ signaling were unaffected. In contrast, marked heterolog ous desensitization of bradykinin-mediated responses occurred despite no re ceptor phosphorylation. This desensitization was associated with a sustaine d component of muscarinic receptor-mediated signaling, whereas bradykinin's inability to influence muscarinic receptor-mediated responses was associat ed with rapid and full desensitization of bradykinin responses. Thus the me chanism 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 desens itization is not obligatory after heterologous receptor phosphorylation.