This subfamily of G protein-coupled receptors consists of PACi, which binds PACAP alone, and VPAC, and VPAC2, which bind PACAP and VIP with equal affinity. These homologous receptors all have a long N-terminal extracellular sequence with five conserved cysteines, as well as conserved other cysteines and basic amino acids in the first and second extracellular loops and third intracellular loop and cytoplasmic tail. There are numerous splice variants of PACi, but not of the VPAC receptors. As for the corresponding ligands, these receptors are distributed preferentially in the nervous system, endocrine and immune organs, intestines and lungs. Signaling through two or more G proteins is mediated principally by increases in [cAMP], and [Ca2+]j. Genetic manipulation of expression of the receptors is now in progress.