Heterodimerization of ORL1 and Opioid Receptors and Its Consequences for N-type Calcium Channel Regulation |
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Authors: | Rhian M Evans Haitao You Shahid Hameed Christophe Altier Alexandre Mezghrani Emmanuel Bourinet and Gerald W Zamponi |
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Institution: | From the ‡Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary T2N 4N1, Canada and ;the §Institut de Génomique Fonctionnelle, CNRS, 34094 Montpellier, France |
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Abstract: | We have investigated the heterodimerization of ORL1 receptors and classical members of the opioid receptor family. All three classes of opioid receptors could be co-immunoprecipitated with ORL1 receptors from both transfected tsA-201 cell lysate and rat dorsal root ganglia lysate, suggesting that these receptors can form heterodimers. Consistent with this hypothesis, in cells expressing either one of the opioid receptors together with ORL1, prolonged ORL1 receptor activation via nociceptin application resulted in internalization of the opioid receptors. Conversely, μ-, δ-, and κ-opioid receptor activation with the appropriate ligands triggered the internalization of ORL1. The μ-opioid receptor/ORL1 receptor heterodimers were shown to associate with N-type calcium channels, with activation of μ-opioid receptors triggering N-type channel internalization, but only in the presence of ORL1. Furthermore, the formation of opioid receptor/ORL1 receptor heterodimers attenuated the ORL1 receptor-mediated inhibition of N-type channels, in part because of constitutive opioid receptor activity. Collectively, our data support the existence of heterodimers between ORL1 and classical opioid receptors, with profound implications for effectors such as N-type calcium channels. |
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Keywords: | N-type Channel Opioid Receptors Heterodimers Nociceptin DAMGO Internalization G Proteins |
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