Résumé : The VPAC(1) receptor belongs to family B of G protein coupled receptors (GPCR-B) and is activated upon binding of the VIP peptide. Despite the recent solving of the structure of the N-terminus of several members of this receptor family, little is known about the structure of the transmembrane (TM) region and about the molecular mechanisms leading to activation. In the present study we designed a new structural model of the TM domain and combined it with experimental mutagenesis experiments to investigate the interaction network that governs ligand binding and receptor activation. Our results suggest that this network involves the cluster of residues R(188) in TM2, Q(380) in TM7 and N(229) in TM3. This cluster is expected to be altered upon VIP binding, as R(188) has previously been shown to interact with D(3) of VIP. Several point mutations at positions 188, 229 and 380 were experimentally characterized and shown to severely affect VIP binding and/or VIP mediated cAMP production. Double mutants built from reciprocal residue exchanges exhibit strong cooperative or anti-cooperative effects, thereby indicating the spatial proximity of residues R(188), Q(380) and N(229). As these residues are highly conserved in the GPCR-B family, they can moreover be expected to have a general role in mediating function.