Jade Degrandmaison – Université de Sherbrooke
Jade Degrandmaison, Khaled Abdallah, Véronique Blais, Samuel Génier, Marie-Pier Lalumière, Francis Bergeron, Catherine M. Cahill, Jim Boulter, Christine L. Lavoie, Jean-Luc Parent, and Louis Gendron. In vivo mapping of a GPCR interactome using knockin mice. Proceedings of the National Academy of Sciences of the United States of America, 117(23):13105-13116, 2020
A study of the interactome of the delta-opioid receptor from brain tissues reveals insights into its functions in pain-related pathways
Given its analgesic properties and milder undesired effects, the delta-opioid receptor (DOPr) represents a promising therapeutic target for chronic pain management. DOPr is a member of a large family of over 800 G protein-coupled receptors (GPCRs), which are involved in the precise regulation of virtually every physiological system. Despite their invaluable pharmacological relevance (approximatively 34% of all current medications target GPCRs), these receptors have proven difficult to study, due to their structural properties, their low abundance, and the lack of specific antibodies. Using newly generated transgenic mouse models and proteomic analyses, Jade Degrandmaison and her colleagues have developed a new approach to overcome these challenges. In this publication, they reveal the first in vivo interactome of a GPCR, namely the delta-opioid receptor (DOPr), from brain tissues.
The DOPr induces analgesic effects and attenuates pain hypersensitivities in several chronic pain models including neuropathic, inflammatory, diabetic, and cancer pain, while producing considerably less undesired effects than most clinical opioid therapeutics. DOPr activation has also been associated with anxiolytic, antidepressant, as well as cardioprotective and neuroprotective effects, thus rendering it an attractive therapeutic target for chronic pain management. Although considered as a highly promising therapeutic target for chronic pain management, the molecular and cellular mechanisms underlying the regulation of the trafficking and signaling of the DOPr remain poorly characterized.
This study, which has led to the identification of proteins potentially modulating its structure, localization and functions thus represents a crucial step toward our understanding of the cellular processes involve in pain-related pathways, as well as in our ultimate attempt to develop potent and better-tolerated analgesics in this time of opioid crisis.
In addition, the mouse lines generated and described in this article represent important new tools to decipher DOPr functions in specific neuron populations and circuits. Since this new approach can be transposed to any other receptors, this work may also be pivotal for the study of other GPCRs in their native physiological environment, thereby providing new insights and applications for the study of several other pathological conditions including cardiovascular diseases, diabetes, and cancer.
Jade Degrandmaison used two novel mouse lines, characterized in the Gendron laboratory by post-doctoral fellow Khaled Abdallah, to reveal the endogenous interactome of the delta-opioid receptor (DOPr), a first-of-kind approach for a GPCR. Using brain tissues from these unique transgenic mice, she developed and validated an approach allowing the identification of several proteins interacting with the DOPr in vivo, thereby providing a list of potential regulators of its physiological functions, including its roles in pain-related pathways.
Jade Degrandmaison significantly contributed to the conceptualization and experimental design of the study, methodology and experimentations, as well as data analysis. She supervised and trained other graduate students who worked on this project. She wrote the manuscript and participated in the response to editorial revision and designed and performed most of the experiments requested by the reviewers during the peer-review process.
This work was presented in several influent international conferences including the International Narcotics Research Conference (INRC) in New York (USA), the Molecular Pharmacology Gordon Research conference in California (USA) and the Great Lake GPCR retreat in Bromont (CAN).
Jade Degrandmaison received a doctoral scholarship award from the Fonds de Recherche Québec-Santé to perform this work. She is currently a PhD candidate in the laboratories of Jean-Luc Parent and Louis Gendron at the Institut de Pharmacologie de Sherbrooke, affiliated to the Université de Sherbrooke.
She has been awarded the «Relève étoile Jacques-Genest» prize from the Fonds de Recherche Québec-Santé, recognizing exceptional research contribution for this publication.
Jade highlights that this research study is the result of an extensive team effort by all authors and would not have been possible without the exceptional guidance, expertise and support from both her supervisors.
Source of funding:
This work was supported by the Quebec Pain Research Network and the Canadian Institutes of Health Research. Collaborators received support from the Fonds de la Recherche du Québec-Santé, the Université de Sherbrooke and the Natural Sciences and Engineering Research Council of Canada. Research was performed in collaboration with University California Los Angeles (UCLA).