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Article: The μ-opioid receptor down-regulates differently from the δ-opioid receptor: Requirement of a high affinity receptor/G protein complex formation

TitleThe μ-opioid receptor down-regulates differently from the δ-opioid receptor: Requirement of a high affinity receptor/G protein complex formation
Authors
Issue Date1997
PublisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org
Citation
Molecular Pharmacology, 1997, v. 52 n. 1, p. 105-113 How to Cite?
AbstractChronic opioid treatment of Neuro(2A) cells stably expressing either δ- opioid receptor (DOR) or μ-opioid receptor (MOR) resulted in agonist- dependent receptor down-regulation. Although there is high homology in the DOR and MOR amino acid sequences, there is an apparent difference in the regulation of the cellular levels of these two receptors. The ability of 24- hr [D-Pen2,D-Pen5]enkephalin (DPDPE) treatment to internalize and down- regulate DORs expressed in Neuro(2A) remained intact after pertussis toxin (PTX) pretreatment, which uncouples the receptor from G proteins. In contrast, the ability of [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO) to internalize and down-regulate MORs in Neuro(2A) cells was completely abolished by PTX pretreatment. The requirement of functional MOR but not DOR in agonist-induced receptor down-regulation was further demonstrated by site- directed mutagenesis of the receptors. When Asp114 in transmembrane 2 of MOR was converted to alanine, the ability was abolished of DAMGO or morphine to inhibit forskolin-stimulated [3H]cAMP production in Neuro(2A) cells stably expressing this mutant receptor. There was a parallel decrease in agonist affinity and elimination of the agonist-induced receptor down-regulation. On the other hand, although the equivalent mutation of Asp95 to alanine in DOR likewise resulted in the inability of DPDPE to inhibit [3H]cAMP production, the ability of DPDPE to down-regulate this mutant receptor after 24-hr treatment was unaffected. This difference in MOR and DOR down-regulation could be caused by the differences in the ability of these two receptors to form high affinity complexes with G proteins. DOR retained the ability to form high affinity complexes even after PTX pretreatment or after mutation of Asp95 in transmembrane 2. In contrast, MOR existed only in the low affinity, uncoupled state after PTX pretreatment or after conversion of Asp114 to alanine. Therefore, in Neuro(2A) cells, agonist-induced opioid receptor down- regulation seems to depend directly on the formation of the high affinity receptor complexes and not on the activation of the receptors and subsequent transduction of the signals.
Persistent Identifierhttp://hdl.handle.net/10722/170284
ISSN
2015 Impact Factor: 3.931
2015 SCImago Journal Rankings: 2.047
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorChakrabarti, Sen_US
dc.contributor.authorYang, Wen_US
dc.contributor.authorLaw, PYen_US
dc.contributor.authorLoh, HHen_US
dc.date.accessioned2012-10-30T06:07:13Z-
dc.date.available2012-10-30T06:07:13Z-
dc.date.issued1997en_US
dc.identifier.citationMolecular Pharmacology, 1997, v. 52 n. 1, p. 105-113en_US
dc.identifier.issn0026-895Xen_US
dc.identifier.urihttp://hdl.handle.net/10722/170284-
dc.description.abstractChronic opioid treatment of Neuro(2A) cells stably expressing either δ- opioid receptor (DOR) or μ-opioid receptor (MOR) resulted in agonist- dependent receptor down-regulation. Although there is high homology in the DOR and MOR amino acid sequences, there is an apparent difference in the regulation of the cellular levels of these two receptors. The ability of 24- hr [D-Pen2,D-Pen5]enkephalin (DPDPE) treatment to internalize and down- regulate DORs expressed in Neuro(2A) remained intact after pertussis toxin (PTX) pretreatment, which uncouples the receptor from G proteins. In contrast, the ability of [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO) to internalize and down-regulate MORs in Neuro(2A) cells was completely abolished by PTX pretreatment. The requirement of functional MOR but not DOR in agonist-induced receptor down-regulation was further demonstrated by site- directed mutagenesis of the receptors. When Asp114 in transmembrane 2 of MOR was converted to alanine, the ability was abolished of DAMGO or morphine to inhibit forskolin-stimulated [3H]cAMP production in Neuro(2A) cells stably expressing this mutant receptor. There was a parallel decrease in agonist affinity and elimination of the agonist-induced receptor down-regulation. On the other hand, although the equivalent mutation of Asp95 to alanine in DOR likewise resulted in the inability of DPDPE to inhibit [3H]cAMP production, the ability of DPDPE to down-regulate this mutant receptor after 24-hr treatment was unaffected. This difference in MOR and DOR down-regulation could be caused by the differences in the ability of these two receptors to form high affinity complexes with G proteins. DOR retained the ability to form high affinity complexes even after PTX pretreatment or after mutation of Asp95 in transmembrane 2. In contrast, MOR existed only in the low affinity, uncoupled state after PTX pretreatment or after conversion of Asp114 to alanine. Therefore, in Neuro(2A) cells, agonist-induced opioid receptor down- regulation seems to depend directly on the formation of the high affinity receptor complexes and not on the activation of the receptors and subsequent transduction of the signals.en_US
dc.languageengen_US
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.orgen_US
dc.relation.ispartofMolecular Pharmacologyen_US
dc.subject.meshAnimalsen_US
dc.subject.meshDiprenorphine - Metabolismen_US
dc.subject.meshDown-Regulationen_US
dc.subject.meshEnkephalin, Ala(2)-Mephe(4)-Gly(5)-en_US
dc.subject.meshEnkephalin, D-Penicillamine (2,5)-en_US
dc.subject.meshEnkephalins - Pharmacologyen_US
dc.subject.meshGtp-Binding Proteins - Physiologyen_US
dc.subject.meshMiceen_US
dc.subject.meshPertussis Toxinen_US
dc.subject.meshReceptors, Opioid, Delta - Analysisen_US
dc.subject.meshReceptors, Opioid, Mu - Analysisen_US
dc.subject.meshTumor Cells, Cultureden_US
dc.subject.meshVirulence Factors, Bordetella - Pharmacologyen_US
dc.titleThe μ-opioid receptor down-regulates differently from the δ-opioid receptor: Requirement of a high affinity receptor/G protein complex formationen_US
dc.typeArticleen_US
dc.identifier.emailYang, W:yangwl@hkucc.hku.hken_US
dc.identifier.authorityYang, W=rp00524en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.pmid9224819-
dc.identifier.scopuseid_2-s2.0-0030742024en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0030742024&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume52en_US
dc.identifier.issue1en_US
dc.identifier.spage105en_US
dc.identifier.epage113en_US
dc.identifier.isiWOS:A1997XK16900015-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridChakrabarti, S=7403254846en_US
dc.identifier.scopusauthoridYang, W=23101349500en_US
dc.identifier.scopusauthoridLaw, PY=26642941100en_US
dc.identifier.scopusauthoridLoh, HH=35497433400en_US

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