DIFFERENTIAL MU-OPIATE RECEPTOR PHOSPHORYLATION AND DESENSITIZATION INDUCED BY AGONISTS AND PHORBOL ESTERS

mu opiate receptors, the principal sites for opiate analgesia and rewa rd, can display compensatory responses to opiate agonist drug administ ration. Agonist-induced K+ channel responses mediated by these recepto rs desensitize when examined in Xenopus oocyte expression systems. Mec hanisms underlying such processes could include phosphorylation events similar to those re ported to desensitize other G protein-linked rece ptors. We used C-terminally directed anti-mu receptor antibodies to im munoprecipitate a phosphoprotein with size appropriate for the mu rece ptor from stably expressing Chinese hamster ovary cells. Phosphorylati on of this mu opiate receptor protein was enhanced approximately 5-fol d by treatment with the mu agonist morphine. The time course and dose- response relationships between mu receptor phosphorylation and agonist -induced desensitization display interesting parallels. Phosphorylatio n of mu opiate receptor protein is also enhanced similar to 5-fold by treatment with the protein kinase C activator phorbol 12-myristate 13- acetate. The protein kinase inhibitor staurosporine blocked the effect of phorbol 12-myristate 13-acetate on mu receptor phosphorylation. Ho wever, staurosporine failed to block morphine-induced phosphorylation. These observations suggest that several biochemical pathways can lead to mu receptor phosphorylation events that may include mechanisms inv olved in mu receptor desensitization.