Domains determining agonist selectivity in chimaeric VIP 2 (VPAC 2 )/PACAP (PAC 1 ) receptors

The VPAC 2 and PAC 1 receptors are closely related members of the Group II G protein‐coupled receptor family. At the VPAC 2 receptor, VIP is equipotent to PACAP‐38 in stimulating cyclic AMP production, whereas at the PAC 1 receptor PACAP‐38 is many fold more potent than VIP. In this study, domains which confer this selectivity were investigated by constructing four chimaeric receptors in which segments of the VPAC 2 receptor were exchanged with the corresponding segment from the PAC 1 receptor. When expressed in COS 7 cells all the chimaeric receptors bound the common ligand [ 125 I]PACAP‐27 and produced cyclic AMP in response to agonists. Relative selectivity for agonists was determined primarily by the amino terminal extracellular domain of the PAC 1 receptor and the VPAC 2 receptor. The interchange of other domains had little effect on the potency of PACAP‐38 or PACAP‐27. For chimaeric constructs with a PAC 1 receptor amino terminal domain, the substitution of increasing portions of the VPAC 2 receptor decreased the potency of VIP yet increased that of helodermin. This suggests that the interaction of VIP/helodermin but not PACAP with the PAC 1 receptor may be influenced (and differentially so) by additional receptor domains.British Journal of Pharmacology (1999) 128 , 934–940; doi: 10.1038/sj.bjp.0702872