The peptide cholecystokinin (CCK) 2 was originally discovered in the gastrointestinal tract (Ivy and Oldberg, 1928) and has been shown to mediate pancreatic secretion and contraction of gallbladder. Then, CCK was described in the mammalian central nervous system (CNS) as a gastrin-like immunoreactive material (Vanderhaeghen et al., 1975), and it is now generally believed to be the most widespread and abundant neuropeptide in the CNS. This peptide, initially characterized as a 33-amino-acid sequence, is present in a variety of biologically active molecular forms derived from a 115-amino-acid precursor molecule (prepro-CCK; Deschenes et al., 1984), such as CCK-58, CCK-39, CCK-33, CCK-22, sulfated CCK-8 [Asp-Tyr (SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] and CCK-7, unsulfated CCK-8 and CCK-7, CCK-5, and CCK-4 (Trp-Met-Asp-Phe-NH2; Fig. 1; Rehfeld and Nielsen, 1995). The presence of CCK in both gut and brain raises the intriguing issue of the evolutionary significance of separate pools of a peptide in two systems originating from different embryonic zones (ie, endoderm and ectoderm, respectively). Receptors for CCK have been pharmacologically classified on the basis of their affinity for the endogenous peptide agonists CCK and gastrin, which share the same COOH-terminal pentapeptide amide sequence but differ in sulfation at the sixth (gastrin) or seventh (CCK) tyrosyl residue. Two types of CCK receptors (type A,“alimentary”, and type B,“brain”) have thus been distinguished. The CCK-A receptor was first characterized using pancreatic acinar cells (Sankaran et al., 1980), whereas the CCK-B receptor, with a different pharmacological profile, was discovered in the brain (CCK-B; Innis and Snyder, 1980b). The gastrin receptor mediating acid secretion in the stomach was initially thought to constitute a third type of high-affinity receptor on the basis of its location and small differences in affinity for CCK and gastrin-like peptides (Song et al., 1993). However, subsequent cloning of gastrin and CCK-B receptors revealed their molecular identity (see later). CCK-A and CCK-B receptor types have been shown to differ by their relative affinity for the natural ligands, their differential distribution, and their molecular structure. The CCK-A receptor binds sulfated CCK with a 500-to 1000-fold higher affinity than sulfated gastrin or nonsulfated CCK

2 Abbreviations: CCK, cholecystokinin; IUPHAR, International Union of Pharmacology; CNS, central nervous system; PKC, protein kinase C; Hpa, 4-hydroxyphenylacetyl; DRG, dorsal root ganglia; PLC, phospholipase C; IP3, inositol triphosphate; GPCR, G proteincoupled receptor; PLA2, phospholipase A2; MAPK, mitogen-activated protein kinase; BH, Bolton-Hunter; TM, transmembrane domain; ECL, extracellular loop; SOS, the product of son of sevenless.