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 almost half the active compounds presently used as therapeutic agents. The objective of our group is to characterize novel signalling pathways involving GPCRs, determine their contribution to physiology, and their involvement in diseases. We focus on receptors expressed in the brain or the immune system.
More than hundred GPCRs are orphan, meaning that they have no known ligand, and often no known biological function. We are searching for the natural ligands of these orphan receptors starting essentially from natural sources, such as tissue extracts and biological fluids. Orphan receptors are expressed in cell lines amenable for fast screening of biological activities. When activities are identified, the bioactive compounds are purified and characterized. Such characterization usually opens a new chapter of physiology. Our group has over the years characterized more than a dozen receptors, including the thyrotropin receptor, adenosine receptors, the chemokine receptor CCR5 and the chemoattractant receptors ChemR23 and FPR3.
A number of specific receptors, among which several receptors identified by the group, are being studied in details in order to determine their role in physiological processes and diseases. This involves in vitro analysis of receptor pharmacology and ligand processing, distribution studies, as well as the analysis of knock-out and transgenic models. Among these, receptors for the leukocyte chemoattractant protein chemerin are being studied for their role in inflammatory processes and tumorigenesis.
Most, if not all, GPCRs are able to form dimers or higher order oligomers. We have contributed to the demonstration that chemokine receptors form both homo- and hetero-oligomers, and demonstrated that oligomerization often involves allosteric interactions between oligomer subunits, changing thereby the pharmacology and/or signaling properties of individual receptors. We continue to study the functional consequences of GPCR oligomerization in terms of pharmacology and G protein coupling specificity.
LAHURA AGUILAR Olga
SIMONS Marie Jeanne
Bondue B, Vosters O, De Nadai P, Glineur S, De Henau O, Luangsay S, Van Gool F, Communi D, De Vuyst P, Desmecht D, Parmentier M (2011). ChemR23 dampens lung inflammation and enhances anti-viral immunity in a mouse model of acute viral pneumonia1. PLOS Pathogens, 7: e1002358.
Devosse D, Dutoit R, Migeotte I, Imbault V, Communi D, Salmon I, Parmentier M (2011). Processing of HEBP1 by cathepsin D gives rise to F2L, the agonist of Formyl Peptide Receptor 3. J Immunol 187:1475-1485.
Sohy D, Yano H, de Nadai P, Urizar E, Guillabert A, Javitch JA, Parmentier M, Springael JY (2009). Hetero-oligomerization of CCR2, CCR5 and CXCR4 and the protean effects of "selective"-antagonists. J Biol Chem 284:31270-31279.
Luangsay S, Wittamer V, Bondue B, De Henau O, Rouger L, Brait M, Franssen JD, de Nadai P, HuauxF, Parmentier M (2009). Mouse ChemR23 is expressed in dendritic cell subsets and macrophages, and mediates an anti-inflammatory activity of chemerin in a lung disease model. J Immunol 183: 6489-6499.
Devosse T, Guillabert A, D'Haene N, Berton A, De Nadai P, Noel S, Brait M, Franssen JD, Sozzani S, Salmon I, Parmentier M (2009). Formyl peptide receptor-like 2 is expressed and functional in plasmacytoid dendritic cells, tissue-specific macrophage subpopulations, and eosinophils. J Immunol 182:4974-4984.
Sohy D, Parmentier M, Springael JY (2007). Allosteric trans-inhibition by specific antagonists in CCR2/CXCR4 heterodimers. J Biol Chem 282:30062-30069.
Springael JY, Nguyen PL, Urizar E, Costagliola S, Vassart G, Parmentier M (2006). Allosteric modulation of binding properties between units of chemokine receptor homo- and hetero-oligomers. Mol Pharmacol. 69:1652-1661.
Laurent P, Becker JAJ, Valverde O, Ledent C, de Kerchove d’Exaerde A, Schiffmann SN, Maldonado R, Vassart G and Parmentier M (2005). The prolactin-releasing peptide acts as a functional antagonist of the opioid system through its receptor GPR10. Nature Neurosciences, 8:1735-1741.
Migeotte I, Riboldi E, Franssen JD, Gregoire F, Loison C, Wittamer V, Detheux M, Robberecht P, Costagliola S, Vassart G, Sozzani S, Parmentier M, Communi D (2005). Identification and characterization of an endogenous chemotactic ligand specific for FPRL2. J Exp Med. 201:83-93.
El-Asmar L, Springael JY, Ballet S, Urizar Andrieu E, Vassart G, Parmentier M (2005). Evidence for negative binding cooperativity within CCR5-CCR2b heterodimers. Mol Pharmacol. 67:460-469
Wittamer V, Franssen JD, Vulcano M, Mirjolet JF, Le Poul E, Migeotte I, Brezillon S, Tyldesley R, Blanpain C, Detheux M, Mantovani A, Sozzani S, Vassart G, Parmentier M, Communi D (2003). Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J Exp Med. 198: 977-985.
Blanpain C, Vanderwinden JM, Cihak J, Wittamer V, Le Poul E, Issafras H, Stangassinger M, Vassart G, Marullo S, Schlondorff D, Parmentier M, Mack M (2002). Multiple active states and oligomerization of CCR5 revealed by functional properties of monoclonal antibodies. Mol Biol Cell 13: 723-737.
Detheux M, Standker L, Vakili J, Munch J, Forssmann U, Adermann K, Pohlmann S, Vassart G, Kirchhoff F, Parmentier M and Forssmann WG (2000). Natural proteolytic processing of hemofiltrate CC chemokine 1 generates a potent CC chemokine receptor (CCR)1 and CCR5 agonist with anti-HIV properties. J. Exp. Med. 192: 1501-1508.
Blanpain C, Lee B, Tackoen M, Puffer B, Boom A, Libert F, Sharron M, Wittamer V, Vassart G, Doms RW, Parmentier M (2000). Multiple nonfunctional alleles of CCR5 are frequent in various human populations. Blood 96: 1638-1645.
Blanpain C, Migeotte I, Lee B, Vakili J, Doranz BJ, Govaerts C, Vassart G, Doms RW and Parmentier M (1999). CCR5 binds multiple CC-chemokines: MCP-3 acts as a natural antagonist. Blood 94 1899-1905.
Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, Böhme GA, Imperato A, Pedrazzini T, Roques BP, Vassart G, Fratta W, Parmentier M (1999). Unresponsiveness to Cannabinoids and Reduced Addictive Effects of Opiates in CB1 Receptor Knock Out Mice. Science 285: 401-404.
Schurmans S, Schiffmann SN, Gurden H, Lemaire M, Lipp HP, Schwam V, Pochet R, Imperato A, Böhme GA and Parmentier M (1997). Impaired regional LTP in calretinin-deficient mice. Proc. Natl. Acad. Sci. USA 94: 10415-10420.
Ledent C, Vaugeois JM, Schiffmann SN, Pedrazzini T, El Yacoubi M, Vanderhaeghen JJ, Costentin J, Heath JK, Vassart G and Parmentier M (1997). Aggressiveness, hypoalgesia and increased blood pressure in mice deficient for the adenosine A2a receptor. Nature 388: 674-678.
Rucker J, Samson M, Doranz BJ, Libert F, Berson JF, Yi Y, Collman RG, Broder CC, Vassart G, Doms RW and Parmentier M (1996). Regions in -Chemokine Receptors CCR5 and CCR2b that Determine HIV-1 Cofactor Specificity. Cell 87: 437-446.
Mollereau C, Simons MJ, Soularue P, Liners F, Vassart G Meunier JC and Parmentier M (1996). Structure, tissue distribution and chromosomal localization of the prepronociceptin gene. Proc. Natl. Acad. Sci. USA 93: 8666-8670.
Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, Saragosti S, Lapouméroulie C, Cogniaux J, Forceille C, Muyldermans G, Verhofstede C, Guy Burtonboy G, Georges M, Imai T, Rana S, Yi Y, Smyth RJ, Collman RG, Doms RW, Vassart G and Parmentier M (1996). Resistance to HIV-1 infection of Caucasian individuals bearing mutant alleles of the CCR5 chemokine receptor gene. Nature 382: 722-725.
Doranz BJ, Rucker J, Yi Y, Smyth RJ, Samson M, Parmentier M, Collman RG, and Doms RW (1996). A dual-tropic, primary HIV-1 isolate that uses both fusin and the -chemokine receptor CKR-5 as entry cofactors. Cell 85: 1149-1158.
Samson M, Labbé O, Mollereau C, Vassart G and Parmentier M (1996). Molecular cloning and functional characterization of a new CC-chemokine receptor gene. Biochemistry 35: 3362-3367.
Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour JL, Guillemot C, Ferrara P, Monsarrat B, Mazarguil H, Vassart G, Parmentier M and Costentin J (1995). Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377: 532-535.
Vanderhaeghen P, Schurmans S, Vassart G and Parmentier M (1993). Olfactory receptors are displayed on dog mature sperm cells. J. Cell Biol. 123 : 1441-1452.
Parmentier M, Libert F, Schurmans, S., Shiffmann S, Lefort A, Eggerickx D, Ledent C, Mollereau C, Gérard C, Perret J, Grootegoed JA, and Vassart G (1992). Expression of members of the putative olfactory receptor gene family in mammalian germ cells. Nature 355: 453-455.
Ledent C, Dumont JE, Vassart G, and Parmentier M (1992). Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism. EMBO J. 11: 537-542.
Ledent C, Parmentier M, and Vassart G (1990). Tissue specific expression and methylation of a thyroglobulin-CAT gene in transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 87: 6176-6180.
Parmentier M, Libert F, Maenhaut C, Lefort A, Gérard C, Perret J, Van Sande J, Dumont JE and Vassart G (1989). Molecular cloning of the thyrotropin receptor. Science 246: 1620-1622.
Libert F, Parmentier M, Lefort A, Dinsart C, Van Sande J, Maenhaut C, Simons MJ. Dumont JE and Vassart G (1989). Selective amplification and cloning of four new members of the G protein-coupled receptor family. Science 244: 569-572.
Postal address: IRIBHM, ULB campus Erasme, 808 route de Lennik, B-1070 Brussels, Belgium
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