title: Sigma 1 receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding.
abstract: sigma Ligands modulate opioid actions in vivo, with agonists diminishing morphine analgesia and antagonists enhancing the response. Using human BE(2)-C neuroblastoma cells that natively express opioid receptors and human embryonic kidney (HEK) cells transfected with a cloned mu opioid receptor, we now demonstrate a similar modulation of opioid function, as assessed by guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTP gamma S) binding, by sigma(1) receptors. sigma Ligands do not compete opioid receptor binding. Administered alone, neither sigma agonists nor antagonists significantly stimulated [(35)S]GTP gamma S binding. Yet sigma receptor selective antagonists, but not agonists, shifted the EC(50) of opioid-induced stimulation of [(35)S]GTP gamma S binding by 3- to 10-fold to the left. This enhanced potency was seen without a change in the efficacy of the opioid, as assessed by the maximal stimulation of [(35)S]GTP gamma S binding. sigma(1) Receptors physically associate with mu opioid receptors, as shown by coimmunoprecipitation studies in transfected HEK cells, implying a direct interaction between the proteins. Thus, sigma receptors modulate opioid transduction without influencing opioid receptor binding. RNA interference knockdown of sigma(1) in BE(2)-C cells also potentiated mu opioid-induced stimulation of [(35)S]GTP gamma S binding. These modulatory actions are not limited to mu and delta opioid receptors. In mouse brain membrane preparations, sigma(1)-selective antagonists also potentiated both opioid receptor and muscarinic acetylcholine receptor-mediated stimulation of [(35)S]GTP gamma S binding, suggesting a broader role for sigma receptors in modulating G-protein-coupled receptor signaling.
authors.affiliation: Laboratory of Molecular Neuropharmacology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Kim
authors.forename: Ivanka
authors.initials: I
authors.lastname: Kovalyshyn
authors.forename: Maxim
authors.initials: M
authors.lastname: Burgman
authors.forename: Claire
authors.initials: C
authors.lastname: Neilan
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Chien
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
mesh_terms: D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism; D005029:Ethylenediamines / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D051379:Mice; D010423:Pentazocine / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D017480:Receptors, sigma / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000097605:Sigma-1 Receptor
chemical_list: D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005029:Ethylenediamines; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D010423:Pentazocine; D043562:Receptors, G-Protein-Coupled; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin