Brief Review Biology of Gut Cholecystokinin and Gastrin Receptors

Abstract

1. The stomach hormone gastrin and the intestinal hormone cholecystokinin (CCK) share a common C-terminal pentapeptide sequence but have different biological roles. Gastrin is the major stimulant of gastric acid secretion and has a growth stimulatory effect on the secretory part of the stomach. The physiological roles of CCK are the stimulation of pancreatic secretion and the contraction of the gall-bladder. 2. Several classes of receptors have been defined for peptides of the gastrin/CCK family. The CCKA receptor on pancreatic acini has a greater affinity for sulfated CCK than for gastrin, while the gastrin/CCKB receptor in gastric mucosa and brain has similar affinities for both gastrin and CCK. Potent and selective antagonists have been developed for both receptor classes. 3. The structures of the CCKA and gastrin/CCKB receptors have been deduced from the nucleotide sequences of cloned cDNA. The receptors, which both belong to the family with seven transmembrane segments, control secretion via similar signalling mechanisms. Occupation of either receptor leads to activation of phospholipase C, with resultant increases in intracellular levels of inositol triphosphate and Ca2+. Mitogenic signalling pathways are also being defined. 4. Recent studies have questioned the previous assumption that gastrin precursors are inactive. Glycine-extended gastrin17 has been shown to stimulate mitogenesis in some cell lines and may also have an autocrine role in the growth of colonic cancers. The receptors involved, which are clearly distinct in binding properties from the CCKA and gastrin/CCKB receptors, have not yet been cloned. Specific antagonists for the novel receptors will be required to define their function in further detail.

Detection and localization of MIP‐3α/LARC/exodus, a macrophage proinflammatory chemokine, and its CCR6 receptor in human pancreatic cancer

“…Activation of some members of the G-protein linked 7-transmembrane receptor family, such as the bombesin or gastrin receptors, is known to enhance the proliferation of some cells (Chu et al, 1996;Van Nieuwenhove et al, 1998;Shulkes and Baldwin, 1997;Rozengurt, 1998). Therefore, we next sought to determine whether Mip-3␣ also modulated pancreatic cancer cell growth.…”

Effects of Amidated Gastrin and Glycine-Extended Gastrin on Cell Proliferation and Crypt Fission in Parenterally and Orally Fed Rats

“…This is the case with tumours seen in Zollinger-Ellison syndrome [9]and in most colon cancer tissues [15]. Glycine-extended gastrin can stimulate mitogenesis in some cell lines and has been implicated in the growth of colonic cancers [16]. If the adenomatous polyposis coli (APC) tumour suppressor gene is mutated, activation of β-catenin occurs and polyps develop.…”

Use of interfering RNA to investigate the role of endogenous gastrin in the survival of gastrointestinal cancer cells

“…However, in GI epithelial cells, processing is incomplete, resulting in secretion of the precursor peptide, progastrin, and a range of intermediate products, of which the most well-characterised is gly-gastrin (Rehfeld et al, 2004). Whereas amidated gastrin acts through the CCK-2 receptor (CCK-2R) (Shulkes and Baldwin, 1997), progastrin and gly-gastrin bind with low affinity to this receptor (Baldwin et al, 2001;Dockray et al, 2001). Furthermore, the biological effects of progastrin and gly-gastrin are not blocked by CCK-B receptor antagonists (Seva et al, 1994;Stepan et al, 1999;Baldwin et al, 2001), and amidated gastrin and gly-gastrin stimulate different downstream signalling events (Todisco et al, 2001).…”