Horm Metab Res 2004; 36(11/12): 735-741
DOI: 10.1055/s-2004-826154
Review
© Georg Thieme Verlag KG Stuttgart · New York

A Centenary of Gastrointestinal Endocrinology

J.  F.  Rehfeld1
  • 1Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Further Information

Publication History

Received 20 July 2004

Accepted without revision 10 August 2004

Publication Date:
18 January 2005 (online)

Abstract

Gastrointestinal hormones are peptides released to circulation from endocrine cells as well as neurons in the gastrointestinal tract. More than 30 hormone genes are currently known to be expressed in the stomach and intestines, which makes the gut the largest endocrine organ in the body. Moreover, cell and molecular biology now makes it feasible to conceive gastrointestinal endocrinology under five general headings: 1) The structural homology groups the hormones into eight families, each of which is assumed to originate from a common ancestral gene; 2) the individual hormone gene often have multiple phenotypes due to alternative splicing of the primary transcript, tandem organization of the translational product or differentiated maturation of the prohormone. By a combination of these mechanisms, more than 100 different hormonally active peptides are released from the gastrointestinal tract; 3) in addition, gut hormone genes are also widely expressed outside the gut, some only in neurons and/or in endocrine cells, but others also in other extraintestinal cell-types; 4) the different cell types may express different hormonally active fragments of the same prohormone by variation in the cell-specific posttranslational processing. Finally, 5) endocrine cells, neurons, and spermatozoa display different cell-specific release of gut peptides, so the same peptide may act as a metabolic blood-borne hormone, as a neurotransmitter, as a long-acting growth factor, and as an acute fertility factor.

References

  • 1 Bayliss W M, Starling E H. The mechanism of pancreatic secretion.  J Physiol. 1902;  28 325 - 353
  • 2 Starling E H. The Croonian lecture on the chemical correlation of the function of the body.  Lancet. 1905;  II 339-341
  • 3 Edkins J S. The chemical mechanism of gastric secretion.  J Physiol. 1906;  34 133-144
  • 4 Ivy A C, Oldberg E. A hormone mechanism for gallbladder contraction and evacuation.  Am J Physiol. 1928;  86 599-613
  • 5 Harper A A, Raper H S. Pancreozymin, a stimulant of the secretion of pancreatic enzymes in extracts of the small intestine.  J Physiol. 1943;  102 115-125
  • 6 Jorpes J E, Mutt V. Cholecystokinin and pancreozymin, one single hormone?.  Acta Physiol Scand. 1966;  66 196-202
  • 7 Rehfeld J F. The new biology of gastrointestinal hormones.  Physiol Rev. 1998;  78 1087-1108
  • 8 Schultz S G, Makhlouf G M, Rauner B B (eds.). Handbook of Physiology. The Gastrointestinal System. Neural and Endocrine Biology. Bethesda, MD; Am Physiol Soc 1989 II: 1-722
  • 9 Walsh J H, Dockray G J (eds.). Gut Peptides. New York; Raven Press 1994: 1-884
  • 10 Taché Y, Goto Y, Ohning G, Yamada T (eds.). Gut-brain Peptides in the new Millennium. Los Angeles; Cure Foundation 2002: 1-522
  • 11 Amara S G, Jonas V, Rosenfeld M G, Onge E S, Evans R M. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products.  Nature. 1982;  298 240-244
  • 12 Gafvelin G, Jörnvall H, Mutt V. Processing of prosecretin: Isolation of a secretin precursor from porcine intestine.  Proc Natl Acad Sci USA. 1990;  87 6781-6785
  • 13 Kopin A, Wheeler M, Nishtani J, Leiter A B. The secretin gene: evolutionary history, alternative splicing and developmental regulation.  Proc Natl Acad Sci USA. 1991;  88 5335-5339
  • 14 Persson P, Håkanson R, Axelson J, Sundler F. Gastrin releases a blood-calcium lowering peptide from the acid producing part of the stomach.  Proc Natl Acad Sci USA. 1989;  86 2834
  • 15 Glover I, Barlow D J, Pitts J E, Wood S P, Tickle I J, Blundell T, Tatemoto K, Kimmel J R, Wollmer A, Strassburger W, Zhang Y S. Conformational studies on the pancreatic polypeptide hormone family.  Eur J Biochem. 1985;  142 379-385
  • 16 Johnsen A H, Rehfeld J F. Cionin: a di-sulfotyrosyl hybrid of cholecystokinin and gastrin from the protochordate, Ciona intestinalis.  J Biol Chem. 1990;  265 3054-3058
  • 17 Anastasi A, Erspamer V, Endean R. Isolation and amino acid sequence of caerulein, the active decapeptide of the skin of Hyla caeruluea.  Arch Biochem Biophys. 1968;  125 57-68
  • 18 Doolittle R F, Feng D-F, Tsang S, Cho F, Little E. Determining divergence times of the major kingdoms of living organisms with a protein clock.  Science. 1996;  271 470-477
  • 19 Johnsen A H. Phylogeny of the Cholecystokinin/gastrin family.  Front Neuroendocrinol. 1998;  19 73-99
  • 20 Rourke I J, Rehfeld J F, Møller M, Johnsen A H. Characterization of the cholecystokinin and gastrin genes from the bullfrog, Rana catesbeiana: evolutionary conservation of primary and secondary sites of gene expression.  Endocrinology. 1997;  138 1719-1727
  • 21 Holzer P. Calcitonin gene-related peptide. In: Walsh JH, Dockray GJ (eds) Gut Peptides: Biochemistry and Physiology. New York; Raven Press 1994: 493-534
  • 22 Nawa H, Kotani H, Nakanishi S. Tissue-specific generation of two preprotachykinin mRNAs from one gene by alternative RNA splicing.  Nature. 1984;  312 729-734
  • 23 Mutt V, Jorpes J E, Magnusson S. Structure of porcine secretin. The amino acid sequence.  Eur J Biochem. 1970;  15 513-519
  • 24 Dockray G J, Varro A, Dimaline R, Wang T. The gastrins, their production and biological activities.  Annu Rev Physiol. 2001;  63 199-139
  • 25 Ørskov C, Bersani M, Johnsen A H, Højrup P, Holst J J. Complete sequences of glucagon-like peptide-I from human and pig small intestine.  J Biol Chem. 1989;  264 12 826-12 829
  • 26 Drucker D J, Erlich P, Asa S L, Brubaker P L. Induction of intestinal epithelial proliferation by glucagon-like peptide 2.  Proc Natl Acad Sci USA. 1996;  93 7911-7916
  • 27 Holst J J, Ørskov C, Nielsen O V, Schwartz T W. Truncated glucagon-like peptide-I, an insulin-releasing hormone from the distal gut.  FEBS Lett. 1987;  211 169-174
  • 28 Bell G I, Santerre R F, Müllenbach G T. Hamster preproglucagon contains the sequence of glucagon and two related peptides.  Nature. 1983;  302 716-718
  • 29 Mojsov S, Weir G C, Habener J F. Insulintropin: Glucagon-like peptide-I (7 - 37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas.  J Clin Invest. 1987;  79 616-619
  • 30 Rehfeld J F. Posttranslational attenuation of peptide gene expression.  FEBS Lett. 1990;  268 1-4
  • 31 Malmström J, Stadil F, Rehfeld J F. Gastrins in tissue: concentrations and component pattern in gastric, duodenal and jejunal mucosa of normal human subjects and patients with duodenal ulcer.  Gastroenterology. 1976;  70 697-703
  • 32 Lüttichau H R, van Solinge W W, Nielsen F C, Rehfeld J F. Developmental expression of the gastrin and cholecystokinin genes in rat colon.  Gastroenterology. 1993;  104 1092-1098
  • 33 Larsson L-I, Rehfeld J F, Håkanson R, Sundler F. Pancreatic gastrin in foetal and neonatal rats.  Nature. 1976;  262 609-610
  • 34 Bardram L, Hilsted L, Rehfeld J F. Progastrin expression in the mammalian pancreas.  Proc Natl Acad Sci USA. 1990;  87 298-302
  • 35 Rehfeld J F. Localization of gastrins to neuro- and adenohypophysis.  Nature. 1978;  271 771-773
  • 36 Larsson L-I, Rehfeld J F. Pituitary gastrins occur in corticotrophs and melanotrophs.  Science. 1981;  213 768-770
  • 37 Rehfeld J F, Hansen H F, Larsson L-I, Stengaard-Pedersen K, Thorn A. Gastrin and cholecystokinin in pituitary neurons.  Proc Natl Acad Sci USA. 1984;  81 1902-1905
  • 38 Uvnäs-Wallensten K, Rehfeld J F, Larsson L-I, Uvnäs B. Heptadecapeptide gastrin in the vagal nerve.  Proc Natl Acad Sci USA. 1977;  74 5707-5710
  • 39 Schalling M, Persson H, Pelto-Huikko M, Ødum L, Ekman P, Gotlieb C, Hökfelt T, Rehfeld J F. Expression and localisation of gastrin mRNA and peptides in human spermatognenic cells.  J Clin Invest. 1990;  86 660-669
  • 40 Bundgaard J R, Vuust J, Rehfeld J F. Tyrosine O-sulfation promotes the proteolytic processing of progastrin.  EMBO J. 1995;  14 3073-3079
  • 41 van Solinge W W, Nielsen F C, Friis-Hansen L, Falkmer U G, Rehfeld J F. Expression but incomplete maturation of progastrin in colorectal cancer.  Gastroenterology. 1993;  104 1099-1107
  • 42 Ciccotosto G D, McLeich A, Hardy K J, Shulkes A. Expression processing and secretion of gastrin in patients with colorectal carcinoma.  Gastroenterology. 1995;  109 1142-1153
  • 43 Seva C, Dickinson C, Yamada T. Growth-promoting effects of glycine-extended progastrin.  Science. 1994;  265 410-412
  • 44 Todisco A, Tekeuchi Y, Seva C, Dickinson C, Yamada T. Gastrin and glycine-extended progastrin processing intermediates induce different programs of early gene activation.  J Biol Chem. 1995;  270 28337-28341
  • 45 Larsson L-I, Goltermann N, De Magistris I, Rehfeld J F, Schwartz T W. Gastric somatostatin cells: morphological substrate for paracrine functions.  Science. 1979;  205 1393-1395
  • 46 Sporn M B, Roberts A B. Autocrine growth factors and cancer.  Nature. 1985;  313 745-747
  • 47 Cutita A F, Carney N, Mulshine J, Moody T W, Fedorke J, Fishler A, Minna J D. Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer.  Nature. 1985;  316 823-826
  • 48 Layton J E, Scanlon D B, Soveny C, Mostyn G. Effects of bombesin antagonists on the growth of small-cell lung cancer cells in vitro.  Cancer Res. 1988;  48 4783-4790
  • 49 Sethi T, Rozengurt E. Gastrin stimulates Ca2+-mobilisation and clonal growth in small cell lung cancer cells.  Cancer Res. 1992;  52 6031-6035
  • 50 Hoosein N M, Kiener P A, Curry R L, Brattain M G. Evidence for autocrine growth stimulation of cultured colon tumor cells by gastrin/cholecystokinin-like peptide.  Exp Cell Res. 1990;  186 15-21
  • 51 Weinstock J, Baldwin G S. Binding of gastrin-17 to human gastric carcinoma cell lines.  Cancer Res. 1988;  48 932-937
  • 52 Blackmore M, Hirst B H. Autocrine stimulation of growth of AR4-2J rat pancreatic tumor cells by gastrin.  Br J Cancer. 1992;  66 32-38
  • 53 Heald E B, Kramer S T, Smith J P. Trophic effects of unsulfated cholecystokinin on mouse pancreas and human pancreatic cancer.  Pancreas. 1992;  7 530-535
  • 54 Persson H, Rehfeld J F, Ericsson A, Schalling M, Pelto-Huikko M, Hökfelt T. Transient expression on the cholecystokinin gene in male germ cells and accumulation of the peptide in the acrosomal granule: possible role of cholecystokinin in fertilization.  Proc Natl Acad Sci USA. 1989;  86 6166-6170
  • 55 Li M, Mbikay M, Nakayama K, Miyata A, Arimura A. Prohormone convertase PC4 processes the precursor of PACAP in the testis.  Ann N Y Acad Sci. 2000;  921 333-339
  • 56 Shintani N, Mori W, Hashimoto H, Imai M, Tanaka K. Tomimoto S, Hirose M, Kawaguchi C, Baba A. Defects in reproductive functions in PACAP-deficient female mice.  Regul Pept. 2002;  109 45-48
  • 57 Mbikay M, Tadros H, Ishida N, Lerner C P, de Lamirande E, Chen A, El-Alfy M, Clermont Y, Seidah N G, Chretien M, Gagnon C, Simpson E M. Impaired fertility in mice deficient for the testicular germ-cell protease PC4.  Proc Natl Acad Sci USA. 1997;  94 6842-6846

J. F. Rehfeld

Dept. Clin. Biochemistry (KB 3014), Rigshospitalet

2100 Copenhagen · Denmark

Phone: +45 3545 3018/-19

Fax: +45 3545 4640

Email: rehfeld@rh.dk

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