Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are two structurally related peptides with pleiotropic physiological effects. Biochemical and cloning experiments have demonstrated that there are two structurally distinct receptors which recognize PACAP and VIP peptides with similar affinities (PACAP/VIP R-1, PACAP/VIP R-2), as well as a receptor that is specific for the PACAP peptide (PACAP-Type 1 receptor). Using a homology-based cloning strategy we have identified PACAP/VIP R-2 receptor in human adipocytes, a tissue which was not previously identified as a target for PACAP and VIP action. This receptor type recognizes PACAP-38 and VIP similar affinity with inhibition concentrations of IC50 = 6.2 +/- 4.8 nM for PACAP-38 and IC50 = 9.4 +/- 4.6 nM for VIP. Like the other two PACAP receptors types, PACAP/VIP R-2 is coupled to cAMP-mediated signal transduction pathway with effective doses ED50 = 3.2 +/- 1.6 nM and ED50 = 2.2 +/- 0.9 nM for PACAP-38 and VIP respectively. Transcripts of the common PACAP/VIP R-2 are also found in human brain and a number of peripheral tissues, such as pancreas, muscle, heart, lund, kidney, stomach and low levels in the liver. Comparison of the tissue distribution of the human PACAP/VIP R-2 to that of the other two types of human PACAP receptors (PACAP-Type 1 and the other common PACAP/VIP R-1) by RNase protection showed that each of the three PACAP receptors is expressed in a unique set of human peripheral tissues. RNA transcripts for all three PACAP receptor types are found in human heart, brain and adipose tissue, while PACAP/VIP R-2 is the only one of these three receptor types that is expressed in the pancreas and skeletal muscle. These results suggest a novel and not yet characterized role for PACAP and VIP peptides in the neuroendocrine regulation of insulin-glucose homeostasis.