Name : COUVINEAU
Surname : Alain
Lab adress : Centre de Recherche Biomédicale Bichat-Beaujon (CRB3)
Faculté de Médecine Xavier Bichat
16, Rue H. Huchard
Tel : +33 157277487 Fax :+33 157277471
Diploma : 1981 Bachelor’s degree of Paris 6 University
1982 Bachelor’s degree (Biochemistry) of Paris 6 University
1983 Master‘s degree (Biochemistry) of Paris 6 University
1984 Master thesis (Pharmacology) of Paris 6 University
1986 PhD of molecular pharmacology of Paris 6 University
Career : 1996- Directeur de Recherche 2eme classe
1991-1996 Chargé de Recherche 2eme classe
1987-1991 Chargé de Recherche 2eme classe
Assigments: 2007- INSERM U773/CRB3 (M. Laburthe)
2005-2006 INSERM U683 (M. Laburthe)
1994-2004 INSERM U410 (M. Laburthe)
1991-1993 INSERM U239 (F. Potet)
1984-1990 INSERM U178 (A. Zweibaum)
1983-1984 INSERM U55 (G. Rosselin)
Scientific award: Jacqueline Besson Award, 1992.
Mediators secreted by the digestive tract (hormones, neuropeptides, proteases) interact with receptors which control the main functions of the digestive epithelium (exocrine secretions, uptake, cellular proliferation, apoptosis). They play an important role in diseases such as inflammation and/or cancer. Our research field is focused on the role of G protein-coupled receptor (GPCR) in chronic intestinal inflammation and colon/pancreas cancer.
The vasoactive intestinal peptide (VIP) is an ubiquist 28 aminoacid neuropeptide with wide distribution in both central and peripheral nervous systems, where it plays important regulatory role in many physiological processes. VIP displays a large spectrum of biological functions including regulation of exocrine secretions, hormone release, foetal development, immune response… In pathophysiology, VIP appears to exert beneficial effect in neuro-degenerative and inflammatory diseases. The mechanism of action of VIP implicates two subtypes of receptors (VPAC1 and VPAC2) which are members of class B GPCRs. The class B receptor family comprises of 15 members including receptors for vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptide (PACAP), secretin, glucagon, glucagon-like peptide-1, glucagon-like peptide-2, growth hormone releasing factor (GRF), gastric inhibitory polypeptide and also includes receptors for peptides which have no sequence homology with VIP including parathyroid hormone, calcitonin, calcitonin gene-related peptide and corticotropin-releasing factor (CRF). The natural ligands of these class B GPCRs strongly influence human physiopathology and have been proposed as promising candidates for the treatment of several diseases. Cloning of the human VPAC1 receptor in our team allowed its extensive studies by site-directed mutagenesis and molecular chimerism providing new insights into the molecular basis of interaction of VIP with its receptor in term of: 1) affinity ; 2) specificity; 3) cellular addressing of the receptor; 4) desensitization of the receptor; 5) association of VPAC1 receptor with RAMP proteins; 6) coupling to adenylyl cyclase. Those studies showed the crucial role of the N-terminal ectodomain (N-ted) of VPAC1 in VIP binding. Using different techniques including photoaffinity labeling, NMR, molecular modeling and dynamic molecular simulation, it has been possible to define how VIP interacts with its receptor. We have shown that most of the VIP molecule the 1-28 (helices α) sequence tightly binds the N-ted part of the receptor which is himself structured as a « Sushi » domain.
The recent development of structural studies of VPAC1 receptor as well as a better understanding of the way by which class B GPCRs are activated should be very helpful for the design of new drugs targeting VIP receptors.