Domains determining agonist selectivity in chimaeric VIP2 (VPAC(2))/PACAP (PAC(1)) receptors

1 The VPAC(2) and PAC(1) receptors are closely related members of the Group If G protein-coupled receptor family. At the VPAC(2) receptor, VIP is equi potent 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, dom ains which confer this selectivity were investigated by constructing four c himaeric receptors in which segments of the VPAC(2) receptor were exchanged with the corresponding segment from the PAC(1) receptor. 2 When expressed in COS 7 cells all the chimaeric receptors bound the commo n ligand [I-125]PACAP-27 and produced cyclic AMP in response to agonists. 3 Relative selectivity for agonists was determined primarily by the amino t erminal extracellular domain of the PAC(1) receptor and the VPAC(2) recepto r. The interchange of other domains had little effect on the potency of PAC AP-38 or PACAP-27. 4 Far chimaeric constructs with a PAC(1) receptor amino terminal domain. th e substitution of increasing portions of the VPAC(2) receptor decreased the potency of VIP yet increased that of helodermin. 5 This suggests that the interaction of VIP/helodermin but not PACAP with t he PAC, receptor may be influenced (and differentially so) by additional re ceptor domains.