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G protein-coupled receptors: from structure to diseases

Research project P6/14 (Research action P6)

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Description :

G protein-coupled receptors (GPCR) represent the largest family among membrane receptors (Bockaert and Pin 1999). They play a major role in a variety of physiological and pathophysiological processes, and constitute the targets for about half the active compounds presently used as therapeutic agents. Working together in the frame of a previous IAP network, the partners of the present program have played a major role in the characterization of many G protein-coupled receptors in yeast, insects and mammalian species. Based on this previous experience, they now set up a partnership that will further study both general and specific aspects of this important gene family, with the ultimate goal of improving human health. The partnership will use specific receptors and receptor subfamilies as models, in order to approach the field of GPCRs as a whole, as many of the studied aspects can apply to the entire family. The key models that will be studied, on which the partners have built their present expertise, include the glycoprotein hormone and chemoattractant receptors in human and mouse, insect neuropeptide receptors and yeast sugar-sensing receptors. The main focuses of the program will be as follows:

Structure of GPCRs, activation mechanisms and ligand-receptor interactions

We will construct three dimensional models of our receptors of interest, on the basis of the single crystal structure presently available (bovine rhodopsin) in order to raise hypotheses regarding ligand-receptor interactions, activation mechanisms and oligomeric organization. We will systematically test these models by mutagenesis studies, and the results of these experiments will be used to improve the models. This approach will be applied to most receptor classes studied, and the modeling aspects will be supported by our foreign partner EU1 (L. Pardo, Barcelona). For selected receptors, the models will also be used as basis for the virtual screening of chemical libraries, in order to develop small molecules with agonist, antagonist or allosteric effector properties.

Oligomerization of GPCRs

GPCRs were initially considered to act as monomers. More recent data have shown that most receptors form dimers if not higher order oligomers. The ability of GPCRs to homo- and heterodimerize will likely change many aspects of pharmacology in general, and the partnership has recently demonstrated allosteric interactions between receptor protomers. We will investigate further, for different classes of receptors, the functional consequences of dimerization, in terms of pharmacology, receptor activation, signaling properties and regulatory pathways, and will explore whether these observations apply to receptors expressed at physiological levels in native cell populations. Chemokine, glycoprotein hormone and yeast sugar-sensing receptors will be the first families studied in this frame.

Signaling cascades of G protein-coupled receptors

Besides the classical pathways activated by GPCRs through heterotrimeric G proteins, a number of additional pathways, some of which are G protein-independent have been described. In addition, the range of signaling cascades activated by a given receptor can vary according to the agonist. Signaling cascades will be studied for yeast sugar-sensing, insect neuropeptide and mammalian chemoattractant receptors, focusing on new pathways and the protein complexes involved in signal transduction.

Functional characterization of specific receptors in physiological processes

A number of specific receptors, among which several receptors identified by the partners over the previous IAP programs, will be studied in details in order to determine their role in physiological processes. This will involve in vitro analysis of receptor pharmacology and ligand processing, distribution studies, as well as in vivo studies and the design of knock-out and transgenic models. We will study, among others, chemoattractant receptors (ChemR23, FPRL2) and a set of mammalian neuromodulatory receptors, neuropeptide receptors in insects, and the glucose/sucrose sensing GPCR system in yeast and Candida albicans.

GPCRs in human diseases and animal disease models

For mammalian receptors, we will further determine their potential involvement in human diseases, with a special focus onto inflammation, cancer, and the neuroendocrine axis. These studies will be conducted both by studying human pathological samples, and by submitting the genetically modified mice to a number of in vivo disease models. These models will be run with the help of a group of pathologists (partner P5). The receptors studied in this frame include glycoprotein hormone, chemoattractant and neuromodulatory receptors. Finally, the influence of allelic variation in GPCR genes or gene clusters in mouse lung disease models will be studied by genetic linkage analysis. If candidate GPCR genes result from this approach, they will be studied more specifically both in human and in mouse models.

Characterization of novel receptors and their ligands

Many orphan receptors for which the ligands and function are still unknown are encoded by the mammalian, insect and yeast genomes (Civelli et al. 1999, Wise et al. 2004). Several partners will focus on the characterization of these receptors, through the identification of their ligand, and the subsequent delineation of their function. In particular, human receptors for new leukocyte chemoattractants, neuropeptides, glycoprotein hormone-like proteins and glucose, insect receptors for neuropeptides, and nutrient-sensing receptors in yeast, will be investigated using evolutionary clues.

Olfactory receptors and evolutionary aspects of the GPCR family

The partnership involves groups specialized in yeast, insect and mammalian receptors. This will bring an evolutionary dimension to the program, with parallel studies of receptor classes in different systems. We intend to interact with another IAP network dedicated to Bioinformatics in order to allow in depth studies of receptor gene families in the growing number of full genomes available in the databases. Correlation between structural and functional evolution of receptor and ligand gene families will be studied in this context. We will also reinitiate an avenue of research dedicated to olfactory receptors. Following years of unsuccessful attempts, the reliable functional expression of olfactory receptors became achievable over the recent years. We will build on this recent evolution, and will start a proteomic program in order to identify new proteins involved in the organization of the signaling complex in olfactory neurons, both in mouse and in insects. The evolutionary aspects of olfactory receptors, associated proteins, and ligand specificity will be considered as well.

Integration in international networks

This program will be linked through several of its members to FP6 European consortia dedicated to the same or related topics. This includes a STREP program “GPCRs” involving partner P1 (as coordinator) and EU1, an integrated project “INNOCHEM”, which includes partners P1 and P4, a network of excellence “EADGENE” incorporating partner P5 and a Marie-Curie Training Network “CANTRAIN” involving partner P3.

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