Differential barcoding of opioid receptors trafficking

Abstract

Over the past several years, studies have highlighted the δ-opioid receptor (DOPr) as a promising therapeutic target for chronic pain management. While exhibiting milder undesired effects than most currently prescribed opioids, its specific agonists elicit effective analgesic responses in numerous animal models of chronic pain, including inflammatory, neuropathic, diabetic, and cancer-related pain. However, as compared with the extensively studied μ-opioid receptor, the molecular mechanisms governing its trafficking remain elusive. Recent advances have denoted several significant particularities in the regulation of DOPr intracellular routing, setting it apart from the other members of the opioid receptor family. Although they share high homology, each opioid receptor subtype displays specific amino acid patterns potentially involved in the regulation of its trafficking. These precise motifs or "barcodes" are selectively recognized by regulatory proteins and therefore dictate several aspects of the itinerary of a receptor, including its anterograde transport, internalization, recycling, and degradation. With a specific focus on the regulation of DOPr trafficking, this review will discuss previously reported, as well as potential novel trafficking barcodes within the opioid and nociceptin/orphanin FQ opioid peptide receptors, and their impact in determining distinct interactomes and physiological responses.

Knock-In Mouse Models to Investigate the Functions of Opioid Receptors in vivo

“…It has been suggested that the region-specific differences in MOPr expression levels between A112 and G112 mice might be attributed to the variation in N-glycan types and contents across the brain (Wang et al, 2012). As reported previously, N-glycosylation of GPCRs, a post-translational modification (PTM) mainly occurring in the ER and Golgi apparatus, plays an important role in the correct folding and maturation of the receptors, thereby impacting their neuronal membrane density (Goth et al, 2020;Lemos Duarte and Devi, 2020;Degrandmaison et al, 2021). Presumably due to the differential expression of glycosyltransferases throughout the mouse brain, N-glycosylation of MOPr has been shown to be variable depending on the brain areas (Matsuhashi et al, 2003;Huang et al, 2008Huang et al, , 2012.…”

“…Interestingly, the fate of the presumed DOPr-MOPr heteromers following ligand exposure resulted in their sorting to the lysosomal compartments (Derouiche et al, 2020). As recently reviewed in Degrandmaison et al (2021), the DOPr displays several particularities regarding the regulation of its trafficking, including its preferential targeting to lysosomes following agonist-induced internalization, as opposed to most GPCRs, including MOPr and KOPr, which are typically recycled efficiently to the neuronal plasma membrane (Ko et al, 1999;Tsao and von Zastrow, 2000;Whistler et al, 2002;Tanowitz and von Zastrow, 2003;Tanowitz et al, 2008;Degrandmaison et al, 2021). Interestingly, this specific ligand-selective cointernalization and sorting of DOPr-MOPr heteromers to lysosomes thus suggests a DOPr-driven mechanism and might also represent a potential approach to fine-tune MOPr-mediated downstream signaling (Derouiche et al, 2020).…”

“…Most importantly, several studies have noted that its agonists produce considerably less undesired effects than most clinically prescribed opioids, thus rendering it an attractive alternative target to the MOPr for chronic pain management (Gallantine and Meert, 2005;Feng et al, 2006;Codd et al, 2009). However, the molecular and cellular mechanisms governing the trafficking and signaling of the DOPr are significantly distinct from most other GPCRs, including MOPr and KOPr, contributing to our limited understanding of its regulation (reviewed in Gendron et al, 2016;Degrandmaison et al, 2021). Consequently, the development of novel genetic tools is crucial in order to investigate its involvement in pathophysiological states and its potential as a therapeutic target.…”

“…Belonging to the class-A GPCRs, the opioid receptors family (OPr), which comprises the mu (µ, MOPr), delta (δ, DOPr) and kappa (κ, KOPr) subtypes, share between 59 and 63% of amino acids sequence identity (Pathan and Williams, 2012;Degrandmaison et al, 2021). Moreover, the nociceptin receptor (NOPr), originally referred to as the κtype 3 opioid receptor, is also closely related to the OPr family (Borsodi et al, 2019).…”

Tackling the opioid crisis: Novel mechanisms and clinical perspectives

“…Efforts to improve the utility of opioid pain therapy have also focused on δ receptors because they may possess a better side effect profile as compared with µ receptor-directed therapies (Quirion et al, 2020). Degrandmaison et al (2021) review trafficking patterns of the δ receptor dictated by precise amino acid motifs (akin to cellular barcodes) that direct receptor transport, internalization, recycling, and degradation. This is complemented by an elegant study from Cahill et al (2020) showing that changes in δ receptor ultrastructural localization and signaling critically modulates affective pain and modality-specific pain hypersensitivity in chronic neuropathic pain.…”