title: Vasoactive intestinal polypeptide VPAC1 and VPAC2 receptor chimeras identify domains responsible for the specificity of ligand binding and activation.
abstract: In order to identify the receptor domains responsible for the VPAC1 selectivity of the VIP1 agonist, [Lys15, Arg16, Leu27] VIP (1-7)/GRF (8-27) and VIP1 antagonist, Ac His1 [D-Phe2, Lys15, Arg16, Leu27] VIP (3-7)/GRF (8-27), we evaluated their binding and functional properties on chimeric VPAC1/VPAC2 receptors. Our results suggest that the N-terminal extracellular domain is responsible for the selectivity of the VIP1 antagonist. Selective recognition of the VIP1 agonist was supported by a larger receptor area: in addition to the N-terminal domain, the first extracellular loop, as well as additional determinants in the distal part of the VPAC1 receptor were involved. Furthermore, these additional domains were critical for an efficient receptor activation, as replacement of EC1 in VPAC1 by its counter part in the VPAC2 receptor markedly reduced the maximal response.
authors.affiliation: Department of Biochemistry and Nutrition, School of Medicine, Université Libre de Bruxelles, Belgium.
authors.forename: M G
authors.initials: MG
authors.lastname: Juarranz
authors.forename: J
authors.initials: J
authors.lastname: Van Rampelbergh
authors.forename: P
authors.initials: P
authors.lastname: Gourlet
authors.forename: P
authors.initials: P
authors.lastname: De Neef
authors.forename: J
authors.initials: J
authors.lastname: Cnudde
authors.forename: P
authors.initials: P
authors.lastname: Robberecht
authors.forename: M
authors.initials: M
authors.lastname: Waelbroeck
mesh_terms: D000262:Adenylyl Cyclases; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D008024:Ligands; D010446:Peptide Fragments / Q000378:metabolism; D018005:Receptors, Vasoactive Intestinal Peptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D008024:Ligands; C110307:PG 97-269; D010446:Peptide Fragments; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D011993:Recombinant Fusion Proteins; D014660:Vasoactive Intestinal Peptide; D000262:Adenylyl Cyclases