title: Differential mu opiate receptor phosphorylation and desensitization induced by agonists and phorbol esters.
abstract: mu opiate receptors, the principal sites for opiate analgesia and reward, can display compensatory responses to opiate agonist drug administration. Agonist-induced K+ channel responses mediated by these receptors desensitize when examined in Xenopus oocyte expression systems. Mechanisms underlying such processes could include phosphorylation events similar to those reported to desensitize other G-protein-linked receptors. We used C-terminally directed anti-mu receptor antibodies to immunoprecipitate a phosphoprotein with size appropriate for the mu receptor from stably expressing Chinese hamster ovary cells. Phosphorylation of this mu opiate receptor protein was enhanced approximately 5-fold 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. Phosphorylation of mu opiate receptor protein is also enhanced approximately 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. However, 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 involved in mu receptor desensitization.
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-8205, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.forename: S
authors.initials: S
authors.lastname: Mackin
authors.forename: F F
authors.initials: FF
authors.lastname: Weight
authors.forename: G R
authors.initials: GR
authors.lastname: Uhl
authors.forename: J B
authors.initials: JB
authors.lastname: Wang
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism; D010766:Phosphorylation; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D000700:Analgesics; D004745:Enkephalins; D010750:Phosphoproteins; D015221:Potassium Channels; D017450:Receptors, Opioid, mu; D011994:Recombinant Proteins; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D013755:Tetradecanoylphorbol Acetate