Cholecystokinin receptors: Introduction

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General

Cholecystokinin (CCK) and gastrin are peptides with important roles in gastrointestinal and neural physiology. CCK was discovered in 1928 by Ivy and Oldberg [14] as a factor released by the small intestine in response to fat ingestion that resulted in gallbladder contraction. Later, Harper and Raper [12] discovered a factor that stimulated pancreatic enzyme secretion, and it was ultimately the work of Mutt and Jorpes at the Karolinska Institutet that demonstrated that both of these activities were present in a single peptide, the 33-amino acid form of CCK [18]. Gastrin was initially described in 1905 by Edkins [10]. When this was isolated and sequenced by Gregory and Tracy [11], it became clear that both hormones shared their carboxyl-terminal heptapeptide amide, an important region for their biological activity. It is of note that the "gastrin-like" activity originally identified in the central nervous system was subsequently identified to be CCK [22], one of the most abundant human brain peptides.

Both CCK and gastrin are linear peptides that occur in a series of molecular forms having different lengths that share their carboxyl-terminal pharmacophoric domains. CCK comes from a 115 amino acid precursor (preproCCK) [6] to yield forms 58, 39, 33, 22, and 8 amino acids in length, all containing a sulfated tyrosine residue seven residues from their carboxyl terminus and all containing a carboxyl-terminal amide. Gastrin, in contrast, comes from a 101-amino acid preprohormone and is processed to yield 34 and 17 amino acid length forms, with each present as sulfated and unsulfated forms, with the tyrosine six residues from their carboxyl terminus being variably sulfated [1]. All gastrins are normally amidated [4].

All of the physiological roles for CCK relate to nutritional homeostasis, with activities to stimulate gallbladder contraction, pancreatic exocrine secretion, gastric emptying, intestinal transit, and satiety [3]. The major physiological role for gastrin is the stimulation of gastric acid secretion [8]. Both hormones have other actions that have been described in pathological states, such as their trophic effects on epithelial targets and cancers [13].

CCK receptor heterogeneity and localisation

There are single and distinct genes that encode for CCK and gastrin receptors [5,15,20-21]. These are now called CCK1 and CCK2 receptors, respectively. They were previously classified as Type A (alimentary) and B (brain), respectively, based on their prominent locations. Both genes are organized similarly, with similar numbers of exons and with analogous exon-intron boundaries. Variable pre-mRNA splicing can yield distinct spliceoforms [7,16]. This can occur in different regions of the brain, in different individuals, and in normal versus neoplastic tissues.

Consistent with the actions described above, CCK1 receptors have been localized to gallbladder muscularis, pancreatic nerves, nerves and muscle along the gastrointestinal tract, and in several discrete areas of the brain [19]. These include the nucleus solitarius, the interpeduncular nucleus, and the nucleus accumbens, as well as the area postrema, the dorsal raphe, the substantia nigra, and the ventral tegmentum. CCK2 receptors have been localized to acid secreting cells in the the oxyntic mucosa of the stomach and extensively throughout the brain [19]. Gastric and central nervous system CCK2 receptors have been shown to represent the same molecule, encoded by a single gene [15].

CCK receptor ligands

Distinct structure-activity relationships exist for CCK1 and CCK2 receptor activation by natural peptide ligands. The structural selectivity of the CCK1 receptor is more discriminating, requiring the carboxyl-terminal heptapeptide amide of all forms of CCK [9]. This includes the sulfated tyrosine residue. Therefore, this receptor binds CCK with high affinity and CCK is highly potent to stimulate it, whereas gastrin peptides bind with low affinity and are weak agonists. For the CCK2 receptor, the minimally active fragment is the carboxyl-terminal tetrapeptide amide that is shared by all gastrin and CCK peptides [17]. It is of interest, therefore, that all of these hormonal peptides have similar affinities and potencies to stimulate the CCK2 receptor.

Many non-peptidyl ligands have been developed for CCK1 and CCK2 receptors [2]. Most of these represent antagonists. The potential therapeutic areas being considered for these agents include anxiety, nociception, appetite control, depression, learning, memory, neuroprotection, drug dependence, and gastrointestinal dysmotility states. None of these agents are currently approved for standard clinical use.

Signal transduction

Both types of CCK receptors are Family A guanine nucleotide-binding protein (G protein)-coupled receptors with seven transmembrane segments and characteristic signatures for this group of receptors. They are closely structurally related and signal similarly, through the Gq group of hetertrimeric guanine nucleotide-binding proteins [23]. Agonist stimulation normally leads to stimulation of phospholipase C and increases in intracellular calcium [23].

References

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2. Berna MJ, Tapia JA, Sancho V, Jensen RT. (2007) Progress in developing cholecystokinin (CCK)/gastrin receptor ligands that have therapeutic potential. Curr Opin Pharmacol, 7: 583-592. [PMID:17997137]

3. Chandra R, Liddle RA. (2007) Cholecystokinin. Curr Opin Endocrinol Diabetes Obes, 14: 63-67. [PMID:17940422]

4. Daugherty D, Yamada T. (1989) Posttranslational processing of gastrin. Physiol Rev, 69: 482-502. [PMID:2648420]

5. de Weerth A, Pisegna JR, Huppi K, Wank SA. (1993) Molecular cloning, functional expression and chromosomal localization of the human cholecystokinin type A receptor. Biochem Biophys Res Commun, 194: 811-818. [PMID:8343165]

6. Deschenes RJ, Lorenz LJ, Haun RS, Roos BA, Collier KJ, Dixon JE. (1984) Cloning and sequence analysis of a cDNA encoding rat preprocholecystokinin. Proc Natl Acad Sci U S A, 81: 726-730. [PMID:6199787]

7. Ding WQ, Kuntz SM, Miller LJ. (2002) A misspliced form of the cholecystokinin-B/gastrin receptor in pancreatic carcinoma: role of reduced sellular U2AF35 and a suboptimal 3'-splicing site leading to retention of the fourth intron. Cancer Res, 62: 947-952. [PMID:11830556]

8. Dockray G, Dimaline R, Varro A. (2005) Gastrin: old hormone, new functions. Pflugers Arch, 449: 344-355. [PMID:15480747]

9. Dong M, Liu G, Pinon DI, Miller LJ. (2005) Differential docking of high-affinity peptide ligands to type A and B cholecystokinin receptors demonstrated by photoaffinity labeling. Biochemistry, 44: 6693-6700. [PMID:15850403]

10. Edkins JS. (1905) On the chemical mechanism of gastric secretion. Proc Roy Soc, B 76: 376-.

11. Gregory RA, Tracy HJ. (1964) The constitution and properties of two gastrins extracted from hog antral mucosa. Gut, 5: 103-114. [PMID:14159395]

12. Harper AA, Raper HS. (1943) Pancreozymin, a stimulant of the secretion of pancreatic enzymes in extracts of the small intestine. J Physiol, 102: 115-125. [PMID:16991584]

13. Hoshi H, Logsdon CD. (1993) Both low- and high-affinity CCK receptor states mediate trophic effects on rat pancreatic acinar cells. Am J Physiol, 265: G1177-G1181. [PMID:8279569]

14. Ivy AC, Oldberg E. (1928) A hormone mechanism for gallbladder contraction and evacuation. Am J Physiol, 86: 599-613.

15. Lee YM, Beinborn M, McBride EW, Lu M, Kolakowski LF, Kopin AS. (1993) The human brain cholecystokinin-B/gastrin receptor. Cloning and characterization. J Biol Chem, 268: 8164-8169. [PMID:7681836]

16. Miller LJ, Holicky EL, Ulrich CD, Wieben ED. (1995) Abnormal processing of the human cholecystokinin receptor gene in association with gallstones and obesity. Gastroenterology, 109: 1375-1380. [PMID:7557108]

17. Morley JS. (1968) Structure-function relationships in gastrin-like peptides. Proc R Soc Lond B Biol Sci, 170: 97-111. [PMID:4385256]

18. Mutt V, Jorpes JE. (1968) Structure of porcine cholecystokinin-pancreozymin. 1. Cleavage with thrombin and with trypsin. Eur J Biochem, 6: 156-162. [PMID:5725809]

19. Noble F, Wank SA, Crawley JN, Bradwejn J, Seroogy KB, Hamon M, Roques BP. (1999) International Union of Pharmacology. XXI. Structure, distribution, and functions of cholecystokinin receptors. Pharmacol Rev, 51: 745-781. [PMID:10581329]

20. Pisegna JR, de Weerth A, Huppi K, Wank SA. (1992) Molecular cloning of the human brain and gastric cholecystokinin receptor: structure, functional expression and chromosomal localization. Biochem Biophys Res Commun, 189: 296-303. [PMID:1280419]

21. Ulrich CD, Ferber I, Holicky E, Hadac E, Buell G, Miller LJ. (1993) Molecular cloning and functional expression of the human gallbladder cholecystokinin A receptor. Biochem Biophys Res Commun, 193: 204-211. [PMID:8503909]

22. Vanderhaeghen JJ, Signeau JC, Gepts W. (1975) New peptide in the vertebrate CNS reacting with antigastrin antibodies. Nature, 257: 604-605. [PMID:1165787]

23. Williams JA. (2001) Intracellular signaling mechanisms activated by cholecystokinin-regulating synthesis and secretion of digestive enzymes in pancreatic acinar cells. Annu Rev Physiol, 63: 77-97. [PMID:11181949]

How to cite this page

To cite this family introduction, please use the following:

Laurence J. Miller, Margery Beinfeld, Quan Chen, Fan Gao, Roger A. Liddle, Jens Rehfeld.
Cholecystokinin receptors, introduction. Last modified on 10/08/2015. Accessed on 16/09/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=15.