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Título: | αN-acetyl β-endorphin Is an endogenous ligand of σ1Rs that regulates Mu-opioid receptor signaling by exchanging G proteins for σ2Rs in σ1R oligomers |
Autor: | Garzón, Javier CSIC ORCID ; Cortés-Montero, Elsa CSIC ORCID; Rodríguez-Muñoz, María; Sánchez-Blázquez, Pilar CSIC ORCID | Palabras clave: | αN-acetyl beta endorphin Sigma receptor types 1 and 2 Mu-opioid receptor Beta endorphin 28–31 G-protein signaling Epsilon receptor |
Fecha de publicación: | 2023 | Editor: | Multidisciplinary Digital Publishing Institute | Citación: | International Journal of Molecular Sciences 24(1): 582 (2023) | Resumen: | The opioid peptide β-endorphin coexists in the pituitary and brain in its αN-acetylated form, which does not bind to opioid receptors. We now report that these neuropeptides exhibited opposite effects in in vivo paradigms, in which ligands of the sigma type 1 receptor (σ1R) displayed positive effects. Thus, αN-acetyl β-Endorphin reduced vascular infarct caused by permanent unilateral middle cerebral artery occlusion and diminished the incidence of N-methyl-D-aspartate acid-promoted convulsive syndrome and mechanical allodynia caused by unilateral chronic constriction of the sciatic nerve. Moreover, αN-acetyl β-Endorphin reduced the analgesia of morphine, β-Endorphin and clonidine but enhanced that of DAMGO. All these effects were counteracted by β-Endorphin and absent in σ1R−/− mice. We observed that σ1Rs negatively regulate mu-opioid receptor (MOR)-mediated morphine analgesia by binding and sequestering G proteins. In this scenario, β-Endorphin promoted the exchange of σ2Rs by G proteins at σ1R oligomers and increased the regulation of G proteins by MORs. The opposite was observed for the αN-acetyl derivative, as σ1R oligomerization decreased and σ2R binding was favored, which displaced G proteins; thus, MOR-regulated transduction was reduced. Our findings suggest that the pharmacological β-Endorphin-specific epsilon receptor is a σ1R-regulated MOR and that β-Endorphin and αN-acetyl β-Endorphin are endogenous ligands of σ1R. | Descripción: | This article belongs to the Special Issue Recent Progress of Opioid Research. | Versión del editor: | https://doi.org/10.3390/ijms24010582 | URI: | http://hdl.handle.net/10261/335228 | DOI: | 10.3390/ijms24010582 | E-ISSN: | 1422-0067 |
Aparece en las colecciones: | (IN) Artículos (IC) Artículos |
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