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Ligands act as pharmacological chaperones and increase the efficiency of δ opioid receptor maturation
Author(s) -
PetäjäRepo Ulla E.,
Hogue Mireille,
Bhalla Suparna,
Laperrière André,
Morello JeanPierre,
Bouvier Michel
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/21.7.1628
Subject(s) - endoplasmic reticulum , receptor , biology , microbiology and biotechnology , chaperone (clinical) , g protein coupled receptor , opioid receptor , signal transduction , er retention , chemical chaperone , protein folding , biochemistry , unfolded protein response , opioid , medicine , pathology , gene , mutant
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 δ 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.