title: Ligands act as pharmacological chaperones and increase the efficiency of delta opioid receptor maturation.
abstract: The endoplasmic reticulum (ER) is recognized as an important site for regulating cell surface expression of membrane proteins. We recently reported that only a fraction of newly synthesized delta opioid receptors could leave the ER and reach the cell surface, the rest being degraded by proteasomes. Here, we demonstrate that membrane-permeable opioid ligands facilitate maturation and ER export of the receptor, thus acting as pharmacological chaperones. We propose that these ligands stabilize the newly synthesized receptor in the native or intermediate state of its folding pathway, possibly by inducing stabilizing conformational constrains within the hydrophobic core of the protein. The receptor precursors that are retained in the ER thus represent fully competent folding intermediates that can be targets for pharmacological intervention aimed at regulating receptor expression and cellular responsiveness. The pharmacological chaperone action is independent of the intrinsic signaling efficacy of the ligand, since both agonists and antagonists were found to promote receptor maturation. This novel property of G protein-coupled receptor ligands may have important implications when considering their effects on cellular responsiveness during therapeutic treatments.
authors.affiliation: Département de Biochimie, Université de Montréal, Montréal, Quebec H3C 3J7, Canada. Ulla.Petaja-Repo@oulu.fi
authors.forename: Ulla E
authors.initials: UE
authors.lastname: Petäjä-Repo
authors.forename: Mireille
authors.initials: M
authors.lastname: Hogue
authors.forename: Suparna
authors.initials: S
authors.lastname: Bhalla
authors.forename: André
authors.initials: A
authors.lastname: Laperrière
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Morello
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
mesh_terms: D020126:Brefeldin A / Q000494:pharmacology; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004743:Enkephalin, Leucine / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D018832:Molecular Chaperones / Q000378:metabolism*; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011498:Protein Precursors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D008024:Ligands; D018832:Molecular Chaperones; D009292:Narcotic Antagonists; D011498:Protein Precursors; D011500:Protein Synthesis Inhibitors; D017465:Receptors, Opioid, delta; D020126:Brefeldin A; D004743:Enkephalin, Leucine; D009271:Naltrexone