A full-length clone encoding the human VIP-2 receptor was isolated from a human placenta cDNA library. The 1317-bp cDNA insert encodes a protein of 438 amino acids which is a member of the seven transmembrane domain G-protein-coupled receptor superfamily. Expression of the human VIP-2 receptor in COS-7 cells confered high affinity binding to [125I] VIP (IC50 = 0.93 nM), which was displaced by unlabeled PACAP-38 (IC50 = 6.2 nM). VIP and PACAP-38 were equipotent in stimulating accumulation of cAMP in COS-7 cells transfected with the human VIP-2 receptor. Northern blot analysis revealed two VIP-2 receptor mRNAs of 4.6 kb and 2.3 kb in size which were expressed predominantly in the human skeletal muscle and to a lesser extent in the human brain, heart, pancreas and placenta.