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Summary of the research program
Background
G protein-coupled receptors
(GPCR) represent the largest family among membrane receptors. 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
tridimensional 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 or antagonist 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. Several partners will focus on the
characterization of these receptors, through the identification of
their ligand, and the subsequent delineation of their function. We will
focus on human receptors for new leukocyte chemoattractants,
neuropeptides, glycoprotein hormone-like proteins and glucose, insect
receptors for neuropeptides, and nutrient-sensing receptors in yeast,
using evolutionary clues in this approach.
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.
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