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Role of Protein Kinase C (PKC) in Agonist‐Induced μ‐Opioid Receptor Down‐Regulation
Author(s) -
Kramer Kenneth H.,
Simon Eric J.,
Simon Eric J.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0720585.x
Subject(s) - diprenorphine , protein kinase c , opioid receptor , receptor , agonist , opioid , chemistry , (+) naloxone , pharmacology , μ opioid receptor , microbiology and biotechnology , endocrinology , sigma 1 receptor , medicine , enkephalin , biology , phosphorylation , biochemistry
: Agonist‐induced down‐regulation of opioid receptorsappears to require the phosphorylation of the receptor protein. However, theidentities of the specific protein kinases that perform this task remainuncertain. Protein kinase C (PKC) has been shown to catalyze thephosphorylation of several G protein‐coupled receptors and potentiate theirdesensitization toward agonists. However, it is unknown whether opioidreceptor agonists induce PKC activation under physiological conditions. Usingcultured SH‐SY5Y neuroblastoma cells, which naturally express μ‐ andδ‐opioid receptors, we investigated whether μ‐opioid receptoragonists can activate PKC by measuring enzyme translocation to the membranefraction. PKC translocation and opioid receptor densities were simultaneouslymeasured by 3 H‐phorbol ester and [ 3 H]diprenorphinebinding, respectively, to correlate alterations in PKC localization withchanges in receptor binding sites. We observed that μ‐opioid agonists havea dual effect on membrane PKC density depending on the period of drugexposure. Exposure for 2‐6 h to [ d ‐Ala 2 , N ‐Me‐Phe 4 , Gly‐ol]enkephalin or morphine promotes thetranslocation of PKC from the cytosol to the plasma membrane. Longer periodsof opioid exposure (>12 h) produce a decrease in membrane‐bound PKC densityto a level well below basal. A significant decrease in[ 3 H]diprenorphine binding sites is first observed at 2 h and continues to decline through the last time point measured (48 h). The opioid receptor antagonist naloxone attenuated both opioid‐mediated PKC translocation and receptor down‐regulation. These results demonstrate that opioids are capable of activating PKC, as evidenced by enhanced translocation of the enzyme to the cell membrane, and this finding suggests that PKC may have a physiological role in opioid receptor plasticity.