TY - JOUR
T1 - μ Opioid receptor phosphorylation, desensitization, and ligand efficacy
AU - Yu, Yunkai
AU - Zhang, Li
AU - Yin, Xixi
AU - Sun, Hui
AU - Uhl, George R.
AU - Wang, Jia Bei
PY - 1997/11/14
Y1 - 1997/11/14
N2 - μ opioid receptors are subject to phosphorylation and desensitization through actions of at least two distinct biochemical pathways: agonist- dependent μ receptor phosphorylation and desensitization induced by a biochemically distinct second pathway dependent on protein kinase C activation (1). To better understand the nature of the agonist-induced μ receptor phosphorylation events, we have investigated the effects of a variety of opiate ligands of varying potencies and intrinsic activities on μ receptor phosphorylation and desensitization. Exposure to the potent full agonists sufentanil, dihydroetorphine, etorphine, etonitazine, and [D-Ala2, MePhe4, Glyo15]enkephalin (DAMGO) led to strong receptor phosphorylation, while methadone, l-α-acetyl-methadone (LAAM), morphine, meperidine, DADL, β-endorphin((1-31)), enkephalins, and dynorphin A((1-17)) produced intermediate effects. The partial agonist buprenorphine minimally enhanced receptor phosphorylation while antagonists failed to alter phosphorylation. Buprenorphine and full antagonists each antagonized the enhanced μ receptor phosphorylation induced by morphine or DAMGO. The rank order of opiate ligand efficacies in producing μ receptor-mediated functional desensitization generally paralleled their rank order of efficacies in producing receptor phosphorylation. Interestingly, the desensitization and phosphorylation mediated by methadone and LAAM were disproportionate to their efficacies in two distinct test systems. This generally good fit between the efficacies of opiates in μ receptor activation, phosphorylation, and desensitzation supports the idea that activated receptor/agonist/G-protein complexes and/or receptor conformational changes induced by agonists are required for agonist- induced μ receptor phosphorylation. Data for methadone and LAAM suggest possible contribution from their enhanced desensitizing abilities to their therapeutic efficacies.
AB - μ opioid receptors are subject to phosphorylation and desensitization through actions of at least two distinct biochemical pathways: agonist- dependent μ receptor phosphorylation and desensitization induced by a biochemically distinct second pathway dependent on protein kinase C activation (1). To better understand the nature of the agonist-induced μ receptor phosphorylation events, we have investigated the effects of a variety of opiate ligands of varying potencies and intrinsic activities on μ receptor phosphorylation and desensitization. Exposure to the potent full agonists sufentanil, dihydroetorphine, etorphine, etonitazine, and [D-Ala2, MePhe4, Glyo15]enkephalin (DAMGO) led to strong receptor phosphorylation, while methadone, l-α-acetyl-methadone (LAAM), morphine, meperidine, DADL, β-endorphin((1-31)), enkephalins, and dynorphin A((1-17)) produced intermediate effects. The partial agonist buprenorphine minimally enhanced receptor phosphorylation while antagonists failed to alter phosphorylation. Buprenorphine and full antagonists each antagonized the enhanced μ receptor phosphorylation induced by morphine or DAMGO. The rank order of opiate ligand efficacies in producing μ receptor-mediated functional desensitization generally paralleled their rank order of efficacies in producing receptor phosphorylation. Interestingly, the desensitization and phosphorylation mediated by methadone and LAAM were disproportionate to their efficacies in two distinct test systems. This generally good fit between the efficacies of opiates in μ receptor activation, phosphorylation, and desensitzation supports the idea that activated receptor/agonist/G-protein complexes and/or receptor conformational changes induced by agonists are required for agonist- induced μ receptor phosphorylation. Data for methadone and LAAM suggest possible contribution from their enhanced desensitizing abilities to their therapeutic efficacies.
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U2 - 10.1074/jbc.272.46.28869
DO - 10.1074/jbc.272.46.28869
M3 - Article
C2 - 9360954
AN - SCOPUS:0030691760
SN - 0021-9258
VL - 272
SP - 28869
EP - 28874
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 46
ER -