Sigma 1 receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding
| Autor: | Maxim Burgman, Felix J. Kim, Ivanka Kovalyshyn, Claire L. Neilan, Gavril W. Pasternak, Chih-Cheng Chien |
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| Rok vydání: | 2010 |
| Předmět: |
Pentazocine
Enkephalin medicine.drug_class Receptors Opioid mu Pharmacology Receptors G-Protein-Coupled Mice Opioid receptor Opioid Receptor Binding Receptors Opioid delta medicine Animals Humans Receptors sigma Receptor Cells Cultured Binding Sites Chemistry Articles Enkephalin Ala(2)-MePhe(4)-Gly(5) Ethylenediamines RGS17 G Protein-Coupled Receptor Signaling Opioid Guanosine 5'-O-(3-Thiotriphosphate) Molecular Medicine Signal transduction medicine.drug Signal Transduction |
| Zdroj: | Molecular pharmacology. 77(4) |
| ISSN: | 1521-0111 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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