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Agonist‐direct Mu‐opioid Receptor Desensitization
Author(s) -
Chu Ji,
Loh Horace H.,
Law PingYee
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a426-c
Subject(s) - homologous desensitization , damgo , desensitization (medicine) , agonist , enkephalin , μ opioid receptor , chemistry , pharmacology , g protein coupled receptor , receptor , endocrinology , opioid receptor , opioid , medicine , biology , biochemistry
Classical theory suggests GPCR homologous desensitization is resulted from activation of GRKs and βarrestins (βArr). As a prototypic GPCR, mechanism of mu‐opioid receptor (MOR) desensitization was examined by measuring agonists potentiating intracellular Ca 2+ releasing ([Ca 2+ ] i ) in the presence of P2Y receptor agonists. Prolonged agonist pretreatment reduced this potentiation, while did not affect P2Y receptor activity, indicating homologous desensitization. MOR full agonist [D‐Ala 2 , N ‐Me‐Phe 4 ,Gly 5 ‐ol]‐enkephalin(DAMGO)‐inducedMOR desensitization within minutes which was βArr‐dependent. Mutation of GRK‐dependent phosphorylation sites in MOR attenuated DAMGO‐induced desensitization. Different from most reports, morphine‐induced desensitization was faster than that of DAMGO, and, this was not affected by GRK sites mutation. Likewise, morphine‐induced desensitization was only partially reduced in βArr1/2 −/− MEF cells, and this desensitization could be further blocked by PKC inhibitor Ro‐31‐8425. In addition, PKC inhibitor also attenuated morphine‐induced MOR desensitization, both in wild type and GRK sites mutant MORs, while PKC inhibitor did not affect DAMGO‐induced MOR desensitization. Therefore, MOR homologous desensitization can occur in multiple pathways, and this is agonist selective. (This research was supported in part by NIDA grant)