Functional, pharmacological, and recent cloning studies have now established that two classes of receptors exist for cholecystokinin (CCK)/gastrin-related peptides (TABLE 1). One class, the CCKA receptor, has a high affinity only for the naturally occurring CCK/gastrinrelated peptides that are sulfated in the seventh position from the COOH-terminus which includes all forms of CCK (CCK-58, CCK-39, CCK-33, and CCK-8), caerulein, and the invertebrate peptide cionin. 1–9 In contrast, the CCKB receptor has high affinity for both CCK peptides and gastrin with sulfation in either the sixth position (cionin, gastrin-17-II) or the seventh position from the COOH-terminus (CCK peptides, caerulein, and cionin), increasing potency less than 10-fold in most studies (TABLE 1). 2, 5, 8–15 Both selective agonists and antagonists were described for each of these receptors (TABLE 1). 2, 3, 16–30

Functional and binding studies as well as studies of the distribution of mRNA for these receptors show that they are widely distributed in the CNS and peripheral tissues (TABLE 1). 3, 31 In an increasing number of tissues such as guinea pig and dog pancreatic acinar cells, guinea pig chief cells, somatostatin-releasing cells of the stomach, gastrointestinal smooth muscle from stomach and gallbladder, in the CNS, and on the pancreatic acinar tumor cell line AR42J, both CCKA and CCKB receptors exist on the same cells. 15, 31–38 In other tissues such as the gastric mucosa, tissue containing both CCK/gastrin receptor subtypes exists in close proximity. 39, 40 Therefore, in assessing changes in biological responses frequently even in single cells, but particularly in assessing in vivo responses to CCK, it is becoming increasingly important to differentiate which effect is mediated by which receptor subtype, because CCK interacts with high affinity with both CCK receptor subtype. 8, 10, 15 Furthermore, activation of CCKA and CCKB receptors may lead to similar responses in some tissues such as somatostatin release from isolated fundi D cells35 or increases in inositol phosphates and [Ca2+] i in AR42J cells, 34 whereas in other tissues such as effects on gastric acid secretion, 40 their activation in the gastric mucosa may have opposing effects. It is therefore becoming increasingly important to differentiate the ability of CCK to activate either subtype.