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Research ArticleArticle

Contribution of Phospholipase C-β3 Phosphorylation to the Rapid Attenuation of Opioid-Activated Phosphoinositide Response

Derek Strassheim, Ping-Yee Law and Horace H. Loh
Molecular Pharmacology June 1998, 53 (6) 1047-1053;
Derek Strassheim
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Ping-Yee Law
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Horace H. Loh
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Abstract

Activation of the δ-opioid receptor in NG108–15 neuroblastoma X glioma hybrid cells results in a transient increase at the intracellular level of inositol-1,4,5-triphosphate [Ins(1,4,5)P3]. This time course in the transient increase in the Ins(1,4,5)P3 level is distinctly different from that observed in the homologous opioid receptor desensitization as measured by the inhibition of adenylyl cyclase activity. One probable mechanism for this rapid loss in Ins(1,4,5)P3 response is the feedback regulation of the phospholipase C activity. Regulation by protein phosphorylation was suggested by the observations that the opioid-mediated response was potentiated by calphostin C, an inhibitor of protein kinase C (PKC), and was abolished by either phorbol-12-myristate-13-acetate, a PKC activator, or calyculin A, a protein phosphatase½A inhibitor. The direct phosphorylation of phospholipase C was demonstrated by immunoprecipitation of PLC-β3 from metabolically labeled NG108–15 cells challenged with the δ-selective agonist [d-Pen2,d-Pen5]enkephalin (DPDPE). A time- and DPDPE concentration-dependent and naloxone-reversible increase in the PLC-β3 phosphorylation can be demonstrated. This PLC-β3 phosphorylation was mainly due to PKC activation because pretreatment of NG108–15 cells with calphostin C could block the DPDPE effect. Activation of the PLC-β3 by DPDPE was one of the prerequisites for agonist-mediated PLC-β3 phosphorylation because the aminosteroid phospholipase C inhibitor U73122 could block the DPDPE effect. In addition to DPDPE, lysophosphatidic acid (LPA) stimulated the PLC-β3 phosphorylation, but bradykinin did not. Furthermore, the LPA- and DPDPE-mediated PLC-β3 phosphorylation was additive and was much less than that observed with phorbol-12-myristate-13-acetate. The effect of DPDPE was specific to PLC-β3; the βγ-insensitive phospholipase C-β1 was not phosphorylated in the presence of either DPDPE or LPA. These results indicate that although PKC phosphorylation of PLC-β3 is not obligatory for the opioid receptor desensitization, it seems to play a significant facilatory role in the mechanisms allowing desensitization of opioid-activated phospholipase C response before that of adenylyl cyclase inhibition.

Footnotes

  • Send reprint requests to: Dr. Ping-Yee Law, Department of Pharmacology, University of Minnesota, 3–249 Millard Hall, 435 Delaware St., S.E., Minneapolis, MN 55455-0347. E-mail:ping{at}lenti.med.umn.edu.

  • This work was supported by National Institutes of Health Grants DA00564, DA01583, DA05695, K05-DA70554, and DA07339 and by the F. and A. Stark Fund of the Minnesota Medical Foundation.

  • Abbreviations:
    DPDPE
    [d-Pen2,d-Pen5]-enkephalin
    GPCR
    G protein-coupled receptor
    Ins(1
    4,5)P3, inositol-1,4,5-triphosphate
    LPA
    lysophosphatidic acid
    PKC
    protein kinase C
    PLC
    phospholipase C
    PMA
    phorbol-12-myristate-acetate
    PVDF
    polyvinylidene difluoride
    SDS
    sodium dodecyl sulfate
    PAGE
    polyacrylamide gel electrophoresis
    • Received September 17, 1997.
    • Accepted February 24, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (6)
Molecular Pharmacology
Vol. 53, Issue 6
1 Jun 1998
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Research ArticleArticle

Contribution of Phospholipase C-β3 Phosphorylation to the Rapid Attenuation of Opioid-Activated Phosphoinositide Response

Derek Strassheim, Ping-Yee Law and Horace H. Loh
Molecular Pharmacology June 1, 1998, 53 (6) 1047-1053;

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Research ArticleArticle

Contribution of Phospholipase C-β3 Phosphorylation to the Rapid Attenuation of Opioid-Activated Phosphoinositide Response

Derek Strassheim, Ping-Yee Law and Horace H. Loh
Molecular Pharmacology June 1, 1998, 53 (6) 1047-1053;
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