In Vivo Visualization of Delta Opioid Receptors upon Physiological Activation Uncovers a Distinct Internalization Profile

Lauren Faget (1) , Eric Erbs (1) , Julie Le Merrer (2) , Gregory Scherrer (3) , Audrey Matifas (1) , Nadia Benturquia (4) , Florence Noble (5, 6, 7) , Marion Decossas (8) , Marc Koch (9) , Pascal Kessler , J.-L. Vonesch (1) , Yannick Schwab (9) , Brigitte L Kieffer (10) , Dominique Massotte (1)

1 IGBMC - Institut de génétique et biologie moléculaire et cellulaire
2 LAM - Laboratoire d'Astrophysique de Marseille
3 ICB - Laboratoire Interdisciplinaire Carnot de Bourgogne
4 VariaPsy - U1144 - Variabilité de réponse aux Psychotropes
5 NAVVEC - UM 81 (UMR 8206/ U705) - Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique
6 UPD5 - Université Paris Descartes - Paris 5
7 UPD5 Pharmacie - Faculté de Pharmacie de Paris - Université Paris Descartes
8 ICT - Immunopathologie et chimie thérapeutique
9 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
10 GEOLAB - Laboratoire de Géographie Physique et Environnementale

G-protein-coupled receptors (GPCRs) mediate numerous physiological functions and represent prime therapeutic targets. Receptor trafficking upon agonist stimulation is critical for GPCR function, but examining this process in vivo remains a true challenge. Using knock-in mice expressing functional fluorescent delta opioid receptors under the control of the endogenous promoter, we visualized in vivo internalization of this native GPCR upon physiological stimulation. We developed a paradigm in which animals were made dependent on morphine in a drug-paired context. When re-exposed to this context in a drug-free state, mice showed context-dependent withdrawal signs and activation of the hippocampus. Receptor internalization was transiently detected in a subset of CA1 neurons, uncovering regionally restricted opioid peptide release. Importantly, a pool of surface receptors always remained, which contrasts with the in vivo profile previously established for exogenous drug-induced internalization. Therefore, a distinct response is observed at the receptor level upon a physiological or pharmacological stimulation. Altogether, direct in vivo GPCR visualization enables mapping receptor stimulation promoted by a behavioral challenge and represents a powerful approach to study endogenous GPCR physiology.

Domaines: Sciences du Vivant [q-bio]

Lauren Faget, Eric Erbs, Julie Le Merrer, Gregory Scherrer, Audrey Matifas, et al.. In Vivo Visualization of Delta Opioid Receptors upon Physiological Activation Uncovers a Distinct Internalization Profile. Journal of Neuroscience, 2012, 32 (21), pp.7301 - 7310. ⟨10.1523/JNEUROSCI.0185-12.2012⟩. ⟨hal-01899922⟩