σ1 Receptor modulation of G-protein-coupled receptor signaling: Potentiation of opioid transduction independent from receptor binding Journal Article


Authors: Kim, F. J.; Kovalyshyn, I.; Burgman, M.; Neilan, C.; Chien, C. C.; Pasternak, G. W.
Article Title: σ1 Receptor modulation of G-protein-coupled receptor signaling: Potentiation of opioid transduction independent from receptor binding
Abstract: σ 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 μ opioid receptor, we now demonstrate a similar modulation of opioid function, as assessed by guanosine 5Y-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding, by σ1 receptors. σ Ligands do not compete opioid receptor binding. Administered alone, neither σ agonists nor antagonists significantly stimulated [35S]GTPγS binding. Yet σ receptor selective antagonists, but not agonists, shifted the EC50 of opioid-induced stimulation of [35S]GTPγS 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 [ 35S]GTPγS binding. σ1 Receptors physically associate with μ opioid receptors, as shown by coimmunoprecipitation studies in transfected HEK cells, implying a direct interaction between the proteins. Thus, σ receptors modulate opioid transduction without influencing opioid receptor binding. RNA interference knockdown of σ1 in BE(2)-C cells also potentiated μ opioid-induced stimulation of [35S] GTPγS binding. These modulatory actions are not limited to μ and δ opioid receptors. In mouse brain membrane preparations, σ1-selective antagonists also potentiated both opioid receptor and muscarinic acetylcholine receptor-mediated stimulation of [ 35S]GTPγS binding, suggesting a broader role for σ receptors in modulating G-protein-coupled receptor signaling. Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics.
Keywords: signal transduction; controlled study; unclassified drug; human cell; drug efficacy; nonhuman; mouse; animals; mice; animal tissue; cells, cultured; haloperidol; opiate; rna interference; drug potency; guanosine derivative; binding site; binding sites; receptors, g-protein-coupled; g protein coupled receptor; mu opiate receptor; receptors, opioid, mu; drug binding; receptor binding; opiate receptor; 1,3 di 2 tolylguanidine; 5' o [3 [s 35]thio]triphosphate; cyclazocine; muscarinic receptor; n [2 (3,4 dichlorophenyl)ethyl] 2 dimethylamino n methylethylamine; n allylnormetazocine; opiate antagonist; pentazocine; sigma 1 opiate receptor; enkephalin, ala(2)-mephe(4)-gly(5)-; ethylenediamines; guanosine 5'-o-(3-thiotriphosphate); receptors, opioid, delta; receptors, sigma
Journal Title: Molecular Pharmacology
Volume: 77
Issue: 4
ISSN: 0026-895X
Publisher: The American Society for Pharmacology and Experimental Therapeutics  
Date Published: 2010-04-01
Start Page: 695
End Page: 703
Language: English
DOI: 10.1124/mol.109.057083
PUBMED: 20089882
PROVIDER: scopus
PMCID: PMC2845939
DOI/URL:
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 20 April 2011" - "CODEN: MOPMA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Claire Neilan
    9 Neilan
  2. Felix J Kim
    7 Kim
  3. Gavril W Pasternak
    296 Pasternak