TY - JOUR T1 - Sigma<sub>1</sub> receptor modulation of G-protein coupled receptor signaling: Potentiation of opioid transduction independent from receptor binding JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.057083 SP - mol.109.057083 AU - Felix J. Kim AU - Ivanka Kovalyshyn AU - Maxim Burgman AU - Claire Neilan AU - Chih-Cheng Chien AU - Gavril W. Pasternak Y1 - 2010/01/20 UR - http://molpharm.aspetjournals.org/content/early/2010/01/20/mol.109.057083.abstract N2 - 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 cells (HEK) transfected with a cloned mu opioid receptor (MOR-1), we now demonstrate a similar modulation of opioid function, as assessed by [35]GTPγS binding, by sigma1 receptors. Sigma ligands do not compete opioid receptor binding. Administered alone, neither sigma agonists nor antagonists significantly stimulated [35]GTPγS binding. Yet, sigma receptor selective antagonists, but not agonists, shifted the EC50 of opioid-induced stimulation of [35]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 [35]GTPγS binding. Sigma1 receptors physically associate with opioid receptors, as shown by co-immunoprecipitation studies in transfected HEK cells, implying a direct interaction between the proteins. Thus, sigma1 receptors modulate opioid transduction without influencing opioid receptor binding. RNAi knockdown of sigma1 in BE(2)-C cells also potentiated mu opioid-induced stimulation of [35]GTPγS binding. These modulatory actions are not limited to mu and delta opioid receptors. In mouse brain membrane preparations, sigma1 selective antagonists also potentiated both opioid receptor and muscarinic acetylcholine receptor mediated stimulation of [35]GTPγS binding, suggesting a broader role for sigma1 receptors in modulating G-protein coupled receptor signaling.The American Society for Pharmacology and Experimental Therapeutics ER -