Physiology of cholecystokinin
- Rodger A Liddle, MD
Rodger A Liddle, MD
- Professor of Medicine
- Duke University Medical School
Cholecystokinin (CCK) is the major hormone responsible for gallbladder contraction and pancreatic enzyme secretion. CCK, like other gastrointestinal hormones, is produced in discrete endocrine cells that line the mucosa of the small intestine . It is also found in the central nervous system and peripheral nerves innervating the intestine. In these locations, CCK probably functions as a neurotransmitter.
The original discovery of CCK in 1928 was based upon the observation that a substance within intestinal extracts stimulated gallbladder contraction in dogs (hence the name cholecystokinin). In 1943, a similar extract (which has been called pancreozymin) was noted to stimulate pancreatic enzyme secretion. However, purification of the hormone and determination of its amino acid sequence showed that the actions on the gallbladder and pancreas were due to the same hormone .
Advances in protein biochemistry, molecular biology, and the development of specific CCK receptor antagonists have increased our understanding of the physiologic and potential pathophysiologic actions of CCK. In humans, physiologic properties of CCK include the ability to stimulate gallbladder contraction, increase pancreatic enzyme secretion, delay gastric emptying, potentiate insulin secretion, and regulate food intake (table 1). In addition, CCK regulates bowel motility and has growth promoting effects on the pancreas in certain animals [3,4].
A number of molecular forms of cholecystokinin (CCK) have been identified in brain, intestine, and blood of experimental animals and humans. The original form of CCK purified was a tritriacontapeptide (CCK-33) . CCK is produced from a single gene, and different molecular forms are the result of posttranslational processing. Molecular forms ranging in size from 4 to 83 amino acids have been identified in tissue and blood with the predominant molecular form being CCK-58, and less commonly CCK-8 and CCK-33. (See "Overview of gastrointestinal peptides in health and disease".)
CCK possesses a five amino acid sequence at the carboxyl terminus that is identical to that of gastrin (figure 1). The carboxyl terminus confers the biologic activity of CCK; as a result, gastrin has weak CCK-like activity and CCK has weak gastrin-like activity. The amino acid sequence similarity has also made assays for CCK difficult, since antibodies specific for the biologically active end of the molecule often crossreact with gastrin, which circulates in the blood at concentrations 10 to 100 times greater than that of CCK . (See "Physiology of gastrin".)
- Polak JM, Bloom SR, Rayford PL, et al. Identification of cholecystokinin-secreting cells. Lancet 1975; 2:1016.
- Jorpes E, Mutt V. Cholecystokinin and pancreozymin, one single hormone? Acta Physiol Scand 1966; 66:196.
- Mutt V. Secretin and cholecystokinin. In: Gastrointestinal Hormones, Mutt V (Ed), Academic Press, San Diego 1988. p.251.
- Liddle RA. Cholecystokinin. In: Gut Peptides: Biochemistry and Physiology, Walsh JH, Dockray GJ (Eds), Raven Press, New York 1994. p.175.
- Mutt V, Jorpes JE. Structure of porcine cholecystokinin-pancreozymin. 1. Cleavage with thrombin and with trypsin. Eur J Biochem 1968; 6:156.
- Rehfeld JF. Cholecystokinin. In: Handbook of Physiology: The Gastrointestinal System, Vol II. Neural and Endocrine Biology, Makhlouf GM (Ed), Oxford University Press, New York 1989. p.337.
- Chandra R, Samsa LA, Vigna SR, Liddle RA. Pseudopod-like basal cell processes in intestinal cholecystokinin cells. Cell Tissue Res 2010; 341:289.
- Meyer DK, Protopapas Z. Studies on cholecystokinin-containing neuronal pathways in rat cerebral cortex and striatum. Ann N Y Acad Sci 1985; 448:133.
- Kopin AS, Mathes WF, McBride EW, et al. The cholecystokinin-A receptor mediates inhibition of food intake yet is not essential for the maintenance of body weight. J Clin Invest 1999; 103:383.
- Wank SA, Harkins R, Jensen RT, et al. Purification, molecular cloning, and functional expression of the cholecystokinin receptor from rat pancreas. Proc Natl Acad Sci U S A 1992; 89:3125.
- Kopin AS, Lee YM, McBride EW, et al. Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc Natl Acad Sci U S A 1992; 89:3605.
- Takiguchi S, Takata Y, Funakoshi A, et al. Disrupted cholecystokinin type-A receptor (CCKAR) gene in OLETF rats. Gene 1997; 197:169.
- Langhans N, Rindi G, Chiu M, et al. Abnormal gastric histology and decreased acid production in cholecystokinin-B/gastrin receptor-deficient mice. Gastroenterology 1997; 112:280.
- Green GM, Lyman RL. Feedback regulation of pancreatic enzyme secretion as a mechanism for trypsin inhibitor-induced hypersecretion in rats. Proc Soc Exp Biol Med 1972; 140:6.
- Owyang C, Louie DS, Tatum D. Feedback regulation of pancreatic enzyme secretion. Suppression of cholecystokinin release by trypsin. J Clin Invest 1986; 77:2042.
- Spannagel AW, Green GM, Guan D, et al. Purification and characterization of a luminal cholecystokinin-releasing factor from rat intestinal secretion. Proc Natl Acad Sci U S A 1996; 93:4415.
- Herzig KH, Schön I, Tatemoto K, et al. Diazepam binding inhibitor is a potent cholecystokinin-releasing peptide in the intestine. Proc Natl Acad Sci U S A 1996; 93:7927.
- Liddle RA. Regulation of cholecystokinin secretion by intraluminal releasing factors. Am J Physiol 1995; 269:G319.
- Owyang C, Logsdon CD. New insights into neurohormonal regulation of pancreatic secretion. Gastroenterology 2004; 127:957.
- Ahrén B, Holst JJ, Efendic S. Antidiabetogenic action of cholecystokinin-8 in type 2 diabetes. J Clin Endocrinol Metab 2000; 85:1043.
- Liddle RA, Morita ET, Conrad CK, Williams JA. Regulation of gastric emptying in humans by cholecystokinin. J Clin Invest 1986; 77:992.
- Sayegh AI. The role of cholecystokinin receptors in the short-term control of food intake. Prog Mol Biol Transl Sci 2013; 114:277.
- Moran TH, Ameglio PJ, Peyton HJ, et al. Blockade of type A, but not type B, CCK receptors postpones satiety in rhesus monkeys. Am J Physiol 1993; 265:R620.
- Moran TH, Sawyer TK, Seeb DH, et al. Potent and sustained satiety actions of a cholecystokinin octapeptide analogue. Am J Clin Nutr 1992; 55:286S.
- Jordan J, Greenway FL, Leiter LA, et al. Stimulation of cholecystokinin-A receptors with GI181771X does not cause weight loss in overweight or obese patients. Clin Pharmacol Ther 2008; 83:281.
- Roses AD. Stimulation of cholecystokinin-A receptors with Gl181771X: a failed clinical trial that did not test the pharmacogenetic hypothesis for reduction of food intake. Clin Pharmacol Ther 2009; 85:362.
- Zerbib F, Bruley Des Varannes S, Scarpignato C, et al. Endogenous cholecystokinin in postprandial lower esophageal sphincter function and fundic tone in humans. Am J Physiol 1998; 275:G1266.
- Smith JP, Solomon TE, Bagheri S, Kramer S. Cholecystokinin stimulates growth of human pancreatic adenocarcinoma SW-1990. Dig Dis Sci 1990; 35:1377.
- Staley J, Jensen RT, Moody TW. CCK antagonists interact with CCK-B receptors on human small cell lung cancer cells. Peptides 1990; 11:1033.
- Rai R, Tewari M, Kumar M, et al. Expression profile of cholecystokinin type-A receptor in gallbladder cancer and gallstone disease. Hepatobiliary Pancreat Dis Int 2011; 10:408.
- Smith JP, Solomon TE. Cholecystokinin and pancreatic cancer: the chicken or the egg? Am J Physiol Gastrointest Liver Physiol 2014; 306:G91.
- Heinricher MM, Neubert MJ. Neural basis for the hyperalgesic action of cholecystokinin in the rostral ventromedial medulla. J Neurophysiol 2004; 92:1982.
- Goussous N, Kowdley GC, Sardana N, et al. Gallbladder dysfunction: how much longer will it be controversial? Digestion 2014; 90:147.
- Doty JE, Pitt HA, Porter-Fink V, Denbesten L. Cholecystokinin prophylaxis of parenteral nutrition-induced gallbladder disease. Ann Surg 1985; 201:76.
- Sitzmann JV, Pitt HA, Steinborn PA, et al. Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans. Surg Gynecol Obstet 1990; 170:25.
- Khan IU, Beck-Sickinger AG. Targeted tumor diagnosis and therapy with peptide hormones as radiopharmaceuticals. Anticancer Agents Med Chem 2008; 8:186.
- Wolkowitz OM, Gertz B, Weingartner H, et al. Hunger in humans induced by MK-329, a specific peripheral-type cholecystokinin receptor antagonist. Biol Psychiatry 1990; 28:169.
- Satake K, Kimura K, Saito T. Therapeutic effects of loxiglumide on experimental acute pancreatitis using various models. Digestion 1999; 60 Suppl 1:64.
- Ochi K, Harada H, Satake K. Clinical evaluation of cholecystokinin-A- receptor antagonist (loxiglumide) for the treatment of acute pancreatitis. A preliminary clinical trial. Study Group of Loxiglumide in Japan. Digestion 1999; 60 Suppl 1:81.
- Wang RY, Ashby CR Jr. actions of CCK in the central nervous system. In: CCK Antagonists in Gastroenterology, Adler G, Beglinger C (Eds), Springer-Verlag, Berlin-Heidelberg 1991. p.44.
- Beltinger J, Hildebrand P, Drewe J, et al. Effects of spiroglumide, a gastrin receptor antagonist, on acid secretion in humans. Eur J Clin Invest 1999; 29:153.
- Rehfeld JF, Federspiel B, Bardram L. A neuroendocrine tumor syndrome from cholecystokinin secretion. N Engl J Med 2013; 368:1165.
- Geracioti TD Jr, Liddle RA. Impaired cholecystokinin secretion in bulimia nervosa. N Engl J Med 1988; 319:683.
- Calam J, Ellis A, Dockray GJ. Identification and measurement of molecular variants of cholecystokinin in duodenal mucosa and plasma. Diminished concentrations in patients with celiac disease. J Clin Invest 1982; 69:218.
- Keel PK, Wolfe BE, Liddle RA, et al. Clinical features and physiological response to a test meal in purging disorder and bulimia nervosa. Arch Gen Psychiatry 2007; 64:1058.
- Srivastava A, Pandey SN, Dixit M, et al. Cholecystokinin receptor A gene polymorphism in gallstone disease and gallbladder cancer. J Gastroenterol Hepatol 2008; 23:970.
- Miller LJ, Holicky EL, Ulrich CD, Wieben ED. Abnormal processing of the human cholecystokinin receptor gene in association with gallstones and obesity. Gastroenterology 1995; 109:1375.
- Miyasaka K, Takiguchi S, Funakoshi A. Cholecystokinin 1A receptor polymorphisms. Curr Top Med Chem 2007; 7:1205.
- Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med 2011; 365:1597.