RT Journal Article
SR Electronic
T1 Allelic Variation S268P of the Human μ-Opioid Receptor Affects Both Desensitization and G Protein Coupling
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 328
OP 334
DO 10.1124/mol.58.2.328
VO 58
IS 2
A1 Koch, Thomas
A1 Kroslak, Thomas
A1 Averbeck, Marco
A1 Mayer, Peter
A1 Schröder, Helmut
A1 Raulf, Evelyn
A1 Höllt, Volker
YR 2000
UL http://molpharm.aspetjournals.org/content/58/2/328.abstract
AB The decrease in μ-opioid receptor activity after chronic agonist exposure (1 μM [d-Ala2,N-MePhe4,Gly-ol5]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative Ca2+/calmodulin-dependent protein kinase II (CaMK II) phosphorylation sites, S261 and S266, by alanines in the third intracellular loop of the rat μ-opioid receptor (rMOR1) confers resistance to CaMK II-induced receptor desensitization. In the present study, we show that the injection of active CaMK II inXenopus laevis oocytes led to the desensitization of S261A but not S266A receptor mutant, indicating that S266 is the primary CaMK II phosphorylation site of the rMOR1. For the corresponding phosphorylation site in the human μ-opioid receptor (hMOR), an allelic variation S268P has been recently identified. After expression in X. laevis oocytes and human embryonic kidney 293 cells, this human S268P receptor and a corresponding rat S266P receptor mutant revealed a loss of CaMK II-induced receptor desensitization and a decreased G protein coupling compared with the wild-type receptors. Our results suggest that serines 266 (rMOR1) and 268 (hMOR) play crucial role in receptor desensitization and signaling and that the allelic variation S268P results in a human receptor type with a weaker but persistent G protein coupling after agonist treatment.