A cluster of Ser/Thr residues at the C-terminus of mu-opioid receptor is required for G protein-coupled receptor kinase 2-mediated desensitization

Neuropharmacology. 2000 Jan 28;39(3):353-63. doi: 10.1016/s0028-3908(99)00174-4.


To investigate the functional role of G protein-coupled receptor kinases (GRK) in homologous desensitization of the mu-opioid receptor, human embryonic kidney (HEK) 293 cells, which express a significant level of GRK2, were stably transfected with the cDNA encoding the rat mu-opioid receptor. Wild-type mu-opioid receptors developed homologous desensitization after 30 min pretreatment with DAMGO ([D-Ala2,N-methyl-Phe4,Gly-ol5]enkephalin), a specific mu-opioid receptor agonist. The ability of mu-opioid receptors to develop homologous desensitization was greatly impaired following the transfection of a cDNA fragment encoding the GRK2(495-689) polypeptide, which is believed to block Gbetagamma-mediated transduction events including the membrane translocation and activation of GRK2. The mu(Cdelta45) receptor, a deletion mutant that lacks 45 C-terminal amino acids, failed to exhibit homologous desensitization after 30 min pretreatment of DAMGO. The mu(Cdelta41) receptor, which differs from the mu(Cdelta45) receptor by having four more Ser/Thr residues (Thr354Ser355Ser356Thr357), developed GRK2-mediated desensitization. These results suggest that homologous desensitization of rat mu-opioid receptors results from the activation of GRK2 and that a cluster of Ser/Thr residues (Thr354Ser355Ser356Thr357) at the intracellular carboxyl tail plays an important role in GRK2-mediated mu-opioid receptor desensitization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / metabolism
  • Analgesics, Opioid / pharmacology
  • Animals
  • Cell Line
  • Cyclic AMP-Dependent Protein Kinases / chemistry
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Drug Tolerance
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / metabolism
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • G-Protein-Coupled Receptor Kinase 2
  • Humans
  • Naloxone / metabolism
  • Narcotic Antagonists / metabolism
  • Rats
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / genetics*
  • Receptors, Opioid, mu / metabolism*
  • Serine / metabolism*
  • Threonine / metabolism*
  • Transfection / genetics
  • beta-Adrenergic Receptor Kinases


  • Analgesics, Opioid
  • Narcotic Antagonists
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Threonine
  • Naloxone
  • Serine
  • Cyclic AMP-Dependent Protein Kinases
  • Grk2 protein, rat
  • beta-Adrenergic Receptor Kinases
  • G-Protein-Coupled Receptor Kinase 2