Chaperone-like effects of cell-permeant ligands on opioid receptors

Abstract

The number of cell surface opioid receptors reflects a delicate balance between biosynthesis pathway and endocytosis pathway. The post-activation endocytic events such as internalization, recycling and degradation have been well-documented; however, only a few studies have been conducted on the regulatory events occurring along the protein biosynthesis pathway, including protein folding, endoplasmic reticulum (ER) export, ER-associated degradation, vesicular trafficking and membrane targeting and insertion. Accumulated in vitro evidence has demonstrated that expression of the opioid receptors, either wild-type or mutated, is subject to regulation by prolonged treatment with cell-permeant ligands that exert their regulatory effects post-transcriptionally. These hydrophobic ligands, both agonists and antagonists, were found to act in the ER like ER-resided molecular chaperones to positively affect stability, folding efficiency and/or ER export rate of newly-synthesized receptor proteins. Moreover, a number of observations demonstrated that long-term opioid antagonists up-regulated the receptors in vivo, in accord with the in vitro findings. Potential therapeutic applications of the chaperone-like function of opioid ligands are discussed.

GABA acts as a ligand chaperone in the early secretory pathway to promote cell surface expression of GABAA receptors

“…It is generally acknowledged that ligand chaperones act as “maturational enhancers” that facilitate protein folding, thus stabilizing native conformations [5,16,45,46,52,56]. It has been speculated that this occurs when ligand binding decreases the energy of activation required for native folding [9] and/or stabilizes conformations within the hydrophobic core [52]. Such chaperone-induced stabilization can release receptors from ER quality control proteins [38,56] and promote the assembly of heteromeric receptors [46].…”

Cognate Ligand Chaperoning: a Novel Mechanism for the Post-translational Regulation of Neurotransmitter Receptor Biogenesis

“…Of relevance to the present paper, a number of neurotransmitter receptors have been observed to undergo pharmacological chaperoning including ligand-gated ion channels, in both the Cys loop and bacterial superfamilies, and G protein-coupled receptors. While early studies of pharmacological chaperones focused on the ability of pharmacological chaperones to rescue the biogenesis and surface expression of ER-retained, disease-associated receptor mutants (Beerepoot et al, 2017 ), it subsequently became clear that the biogenesis of recombinant wild type receptors, such as the δ-opioid, dopamine D4, β1-adrenergic, serotonin 5-HT2, adenosine A2, nicotinic acetylcholine, and GABA A receptors was also facilitated by pharmacological chaperones (Petaja-Repo et al, 2000 , 2002 ; Janovick et al, 2002 ; Kuryatov et al, 2005 ; Sallette et al, 2005 ; Corringer et al, 2006 ; Van Craenenbroeck et al, 2006 ; Chen and Liu-Chen, 2009 ; Kobayashi et al, 2009 ; Lester et al, 2009 ; Eshaq et al, 2010 ; Srinivasan et al, 2011 ; Kusek et al, 2015 ). Thus, pharmacological chaperoning provides proof-of-concept that small, receptor-specific ligands can drive neurotransmitter receptor biogenesis and supports the possibility that neurotransmitters themselves, if present in the ER lumen, may regulate the biogenesis of their cognate receptors.…”

Progressive Familial Intrahepatic Cholestasis

“…A pharmacological chaperone is defined as a small molecule that specifically binds to its target protein and induces or promotes proper folding and trafficking of the protein [88]. Some researchers have investigated the usefulness of pharmacological chaperones for treatment of diseases caused by folding-defective membrane proteins [24,89,90]. Pharmacological chaperones such as 4-phenylbutyrate acid (4-PBA) have been shown to stabilize proteins misfolded due to missense mutations, thereby preventing degradation in the endoplasmic reticulum.…”