Discussion: Pancreatic Pathology

This section, entitled "Pancreatic Pathology," includes a spectrum of topics on normal and abnormal pancreatic tissue. Specifically, two presentations deal with characterization of cholecystokinin (CCK) receptors on normal tissues. Wank has recently reported the purification, cloning, and expression of the CCKA receptor from rat pancreas, and the article by Miller deals with the biochemical characterization of the CCKA receptor, primarily in gallbladder and pancreatic membranes. The article by Logsdon et al. deals with the effects of CCK on activating immediate early gene expression in normal pancreas, and the other with pancreatic cancer, including recent results of studies in animal models of pancreatic carcinoma (by Longnecker et al.) and the relationship between pancreatic cancer and diabetes mellitus (by Pour and colleagues). Before considering a few concluding remarks on each paper and points that arose in the questions, because a significant proportion of the papers deal with CCK receptors, Table 1 is included, which summarizes a number of points about the classification of CCK receptors that should be kept in mind in assessing these presentations. CCK and gastrin share the same COOH terminal pentapeptide, and they cause changes in biologic activity or interaction with receptors in binding experiments examining different relative affinities with a number of tissues [1,2]. It is generally agreed, from numerous pharmacological studies, that there are at least two classes of CCK/gastrin receptors [2,3]; one is a CCKA subtype, which interacts with high affinity only with CCK/gastrin analogs sulfated in the seventh position from the COOH terminus. Because gastrin, even when sulfated (gastrin-17-II) is sulfated in the sixth position from the COOH terminus, this receptor has a low affinity for all forms of gastrin [3,4]. This receptor is thought to be the physiologically important receptor mediating the action of CCK on gallbladder contraction, pancreatic secretion, and satiety [1,2,5,6]. Both selective agonists and antagonists now exist for the CCKA subtype; this subtype is found on a number of other tissues, as shown in Table 1, and in the central nervous system (CNS) is present in only a few specific locations, such as the area postrema, certain intrapenduncular nuclei, and the nucleus tractus solitarius [6,7]. Extensive studies have demonstrated that occupation of this receptor causes activation of phospholipase C with changes in cellular calcium and phosphoinositides [2,8]. It is unclear at present whether one subtype, a CCKB/gastrin, or two subtypes, a CCKB and a gastrin receptor, or more, mediate the high-affinity interactions with gastrin and non-sulfated CCK analogs seen in the CNS and various tissues (Table 1) [2,3]. The CCKB receptor was characterized primarily in the CNS by binding studies, where it is widely distributed, especially in the cerebral cortex, and is distinguished by having a high affinity for CCK, gastrin, and various antagonists