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A New Approach to Visualize Endogenously Expressed G Protein-Coupled Receptors in Tissues and Living Cells

  • Grégory Scherrer
  • Brigitte L. Kieffer
Protocol
Part of the Neuromethods book series (NM, volume 60)

Abstract

G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors. These proteins respond to a broad diversity of environmental stimuli and ligands, modulate most physiological processes, and represent prime therapeutic targets. Detecting GPCRs in vivo, however, remains a challenge and this limitation hampers our knowledge of receptor physiology. Autoradiographic ligand binding procedures provide low-resolution information, and the development of specific antibodies for immunohistochemistry has proven difficult. Tagged GPCRs have mainly been used in heterologous overexpression systems and cellular models. Here we describe an innovative approach where a fluorescent protein is fused to a GPCR in vivo. Using a knockin methodology, one can produce mutant mice that express a functional fluorescent receptor in place of the native receptor, and at physiological levels. We have pioneered this approach with the delta opioid receptor, implicated in both pain and emotional disorders. Here we describe these unique knockin reporter mice, and address potential pitfalls of the strategy. We report our first observations using this tool, and exemplify its usefulness at the level of receptor anatomy, function, and adaptations to drugs, with a particular focus on pain processes. This approach is potentially applicable to any GPCR, using an increasing choice among fluorescent reporter proteins, and offers unprecedented perspectives toward understanding GPCR biology and developing novel drugs of therapeutic interest.

Key words

Green fluorescent protein Delta opioid receptor Knockin mouse G protein-coupled receptors Pain Anxiety Depression Trafficking 

Notes

Acknowledgments

We would like to thank Allan Basbaum for initiating the project with us, and for his support and mentoring (GS) in revisiting some aspects of DOR anatomy and function in pain processing. We would like to acknowledge the essential implication of Amynah Pradhan in the behavioral desensitization aspect of these studies, and thank her for her contribution. We thank Petra Tryoen-Toth for her contribution in the initial characterization of mutant mice. We thank Claire Gavériaux-Ruff and Shannon Shields for critical reading and comments. We thank JL Vonesch and the IGBMC Imaging Platform. Research (BK) was supported by the CNRS, INSERM, the Université de Strasbourg, the ANR grant IMOP, the NIH NIDA grant #DA05010, and the Shirley and Stefan Hatos Neuroscience Research Foundation. AP was supported by INSERM-FRSQ. GS was recipient of doctoral grants from French Research Ministry and Fondation pour la Recherche Médicale and was supported by Fondation pour la Recherche Médicale and NIH grants NS14627 and NS48499 during his postdoc in Allan Basbaum laboratory.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Grégory Scherrer
  • Brigitte L. Kieffer
    • 1
  1. 1.Département Neurobiologie et GénétiqueInstitut de Génétique et de Biologie Moléculaire et Cellulaire, Parc d’innovationIllkirchFrance

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