We have isolated a cDNA from a human liver library which is 2349 base pairs in length and encodes a near-full length seven transmembrane receptor (432 amino acids), 85% homologous to the amino acid sequence for the rat vasoactive intestinal peptide (VIP) receptor. Northern blot analysis identifies a major species at 3.3 kb in lung, and to a lesser extent in brain, heart and liver. In order to confirm the identity of this human clone, double-stranded oligonucleotides encoding the signal peptide of the rat VIP receptor were constructed by polymerase chain reaction and attached to the 5' end of the human clone. COS cells transiently transfected with this human VIP receptor chimera, express a single binding site for 125I-VIP with a Kd of 9.2 +/- 2 nM. Related peptides displace 125I-VIP with a relative potency of VIP = PACAP > helodermin >> PHM > secretin, which is similar to the binding profile seen in human tissues. This human chimeric receptor is functionally coupled to the stimulation of adenylyl cyclase in transfected COS cells, as evidenced by a dose-dependent increase in intracellular cAMP accumulation. These studies indicate that this cDNA encodes a human liver VIP receptor which is functionally coupled to the activation of adenylyl cyclase.