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FIGURE 4.29. (A) Pancreas resection specimen from a large mucinous cystadenoma was opened to
show the trabeculated cyst lumen. (B) Microscopically, the cyst wall shows ovarian-type stroma. This
rare tumor tends to occur more commonly in women. (Courtesy of Linda D. Ferrell, MD.)
C linical M anagement .......................................................................................................................... 129
FIGURE 4.30. Cystic neoplasm. In patients with a history of pancreatitis, increased serum amylase
levels, and CT findings characteristic of pancreatitis, such lesions are suggestive of benign pseudocyst.
Neoplasm can be ruled out definitively with biopsy. These cystic neoplasms have septa and some have
central calcification (arrows). (Courtesy of Henry I. Goldberg, MD.)
REFERENCES
1. Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl
J Med 1995;332:1482–1490.
2. Baron TH, Morgan DE. Acute necrotizing pancreatitis. N Engl J
Med 1999;340:1412–1417.
3. Sherman S, Lehman GA. ERCP- and endoscopic sphincterotomy-induced pancreatitis. Pancreas 1991;6:350–367.
4. Beger HG, Buchler M, Bittner R, et al. Necrosectomy and postoperative local lavage in patients with necrotizing pancreatitis:
results of a prospective clinical trial. World J Surg 1988;
12:255–262.
5. Bittner R, Block S, Buchler M, et al. Pancreatic abscess and
infected pancreatic necrosis. Different local septic complications
in acute pancreatitis. Dig Dis Sci 1987;32:1082–1087.
6. Sarles H, Bernard JP, Johnson C. Pathogenesis and epidemiology of chronic pancreatitis. Annu Rev Med 1989;40:453–468.
7. Johnson CD, Hosking S. National statistics for diet, alcohol consumption, and chronic pancreatitis in England and Wales,
1960–88. Gut 1991;32:1401–1405.
8. Yeo CJ, Cameron JL. Pancreatic cancer. Curr Probl Surg 1999
Feb;36:59–152.
9. Luiten EJ, Hop WC, Lange JF, et al. Controlled clinical trial of
selective decontamination for the treatment of severe acute
pancreatitis. Ann Surg 1995;222:57–65.
10. Pederzoli P, Bassi C, Vesentini S, et al. A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications
in acute necrotizing pancreatitis with imipenem. Surg Gynecol
Obstet 1993;176:480–483.
11. Sainio V, Kemppainen E, Puolakkainen P, et al. Early antibiotic
treatment in acute necrotising pancreatitis. Lancet 1995;
346:663–667.
12. D’Egidio A, Schein M. Percutaneous drainage of pancreatic
pseudocysts: a prospective study. World J Surg 1992;16:141–146.
13. Smits ME, Badiga SM, Rauws EA, et al. Long-term results of
pancreatic stents in chronic pancreatitis. Gastrointest Endosc
1995;42:461–467.
14. Greenlee HB, Prinz RA, Aranha GV. Long-term results of sideto-side pancreaticojejunostomy. World J Surg 1990;14:70–76.
15. Ihse I, Borch K, Larsson J. Chronic pancreatitis: results of operations for relief of pain. World J Surg 1990;14:53–58.
16. Buchler MW, Friess H, Muller MW, et al. Randomized trial of
duodenum-preserving pancreatic head resection versus
pylorus-preserving Whipple in chronic pancreatitis. Am J Surg
1995;169:65–70.
17. Cameron JL. Long-term survival following pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas.
Surg Clin North Am 1995;75:939–951.
18. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann
Surg 1995;221:721–733.
19. Lillemoe KD, Barnes SA.Surgical palliation of unresectable pancreatic carcinoma. Surg Clin North Am 1995;75:953–968.
SELECTED READINGS
Acute Pancreatitis
Ashley SW, Perez A, Pierce EA, et al. Necrotizing pancreatitis: con-
temporary analysis of 99 consecutive cases. Ann Surg 2001;234:
527–580.
Bassi C, Falconi M, Talamini G, et al. Controlled clinical trial of
pefloxacin versus imipenem in severe acute pancreatitis. Gas-
troenterology 1998;115:1513–1517.
130 ........................................................................................................................................... Pancreas
S elected R eadings............................................................................................................................... 131
Bradley EL 3rd, Allen K. A prospective longitudinal study of obser-
vation versus surgical intervention in the management of necrotizing pancreatitis. Am J Surg 1991;161:19–25.
Brown A, Baillargeon JD, Hughes MD, et al. Can fluid resuscitation
prevent pancreatic necrosis in severe acute pancreatitis? Pan-
creatology 2002;2:104–107.
Buchler MW, Gloor B, Muller CA, et al. Acute necrotizing pancre-
atitis: treatment strategy according to the status of infection.
Ann Surg 2000;232:619–626.
Folsch UR, Nitsche R, Ludtke R, et al. Early ERCP and papillotomy
compared with conservative treatment for acute biliary pancreatitis. The German Study Group on Acute Biliary Pancreatitis.
N Engl J Med 1997;336:237–242.
Gerzof SG, Banks PA, Robbins AH, et al. Early diagnosis of pancre-
atic infection by computed tomography-guided aspiration.
Gastroenterology 1987;93:1315–1320.
Lee SP, Nicholls JF, Park HZ. Biliary sludge as a cause of acute pan-
creatitis. N Engl J Med 1992;326:589–593.
London NJ, Leese T, Lavelle JM, et al. Rapid-bolus contrast-
enhanced dynamic computed tomography in acute pancreatitis:
a prospective study. Br J Surg 1991;78:1452–1456.
McKay CJ, Imrie CW. Staging of acute pancreatitis. Is it important?
Surg Clin North Am 1999;79:733–743.
Ranson JH, Rifkind KM, Roses DF, et al. Prognostic signs and the
role of operative management in acute pancreatitis. Surg
Gynecol Obstet 1974;139:69–81.
Steinberg W, Tenner S. Acute pancreatitis. N Engl J Med 1994;
330:1198–1210.
Chronic Pancreatitis
Ammann RW, Heitz PU, Kloppel G. Course of alcoholic chronic
pancreatitis: a prospective clinicomorphological long-term
study. Gastroenterology 1996;111:224–231.
Leung JW, Bowen-Wright M, Aveling W, et al. Coeliac plexus block
for pain in pancreatic cancer and chronic pancreatitis. Br J Surg
1983;70:730–732.
Nealon WH, Townsend CM Jr, Thompson JC. Preoperative endo-
scopic retrograde cholangiopancreatography (ERCP) in patients
with pancreatic pseudocyst associated with resolving acute and
chronic pancreatitis. Ann Surg 1989;209:532–540.
Reinhold C. Magnetic resonance imaging of the pancreas in 2001. J
Gastrointest Surg 2002;6:133–135.
Sakorafas GH, Tsiotou AG. Proximal pancreatectomy in the surgical
management of chronic pancreatitis. J Clin Gastroenterol 2002;
34:72–76.
Sarles H, Adler G, Dani R, et al. The pancreatitis classification of
Marseilles-Rome 1988. Scand J Gastroenterol 1989;24:641–642.
Sharer N, Schwarz M, Malone G, et al. Mutations of the cystic fibro-
sis gene in patients with chronic pancreatitis. N Engl J Med
1998;339:645–652.
Witt H, Becker M. Genetics of chronic pancrestitis. J Pediatr Gas-
troenterol Nutr 2002;34:125–136.
Witzigmann H, Mark D, Uhlmarn D, et al. Quality of life in ohronic
pancreatitis: a prospective trial comparing classical Whipple
procedure and duodenum-preserving pancreatic head resection. J Gastrointest Surg 2002;6:173–180.
Pseudocysts
Adler J, Barkin JS. Management of pseudocysts, inflammatory
masses, and pancreatic ascites. Gastroenterol Clin North Am
1990;19:863–871.
Frantzides CT, Ludwig KA, Redlich PN. Laparoscopic management
of a pancreatic pseudocyst. J Laparoendosc Surg 1994;4:55–59.
Spivak H, Galloway JR, Amerson JR, et al. Management of pancre-
atic pseudocysts. J Am Coll Surg 1998;186:507–511.
Vitas GJ, Sarr MG. Selected management of pancreatic pseudocysts:
operative versus expectant management. Surgery 1992;111:
123–130.
Yeo CJ, Bastidas JA, Lynch-Nyhan A, et al. The natural history of
pancreatic pseudocysts documented by computed tomography.
Surg Gynecol Obstet 1990;170:411–417.
Pancreatic Tumors
Birk D, Beger HG. Neoadjuvant, adjuvant, and palliative treatment
of pancreatic cancer. Curr Gastroenterol Rep 2001;3:129–135.
Brennan MF, Moccia RD, Klimstra D. Management of adenocarci-
noma of the body and tail of the pancreas. Ann Surg 1996;
223:506–512.
Ghaneh P, Kawesha A, Howes N, et al. Adjuvant therapy for pancre-
atic cancer. World J Surg 1999;23:937–945.
Glimelius B. Chemotherapy in the treatment of cancer of the pan-
creas. J Hepatobiliary Pancreat Surg 1998;5:235–241.
Hilgers W, Kern SE. Molecular genetic basis of pancreatic adeno-
carcinoma. Genes Chrom Cancer 1999;26:1–12.
Lichtenstein DR, Carr-Locke DL. Endoscopic palliation for unre-
sectable pancreatic carcinoma. Surg Clin North Am
1995;75:969–988.
Lillemoe KD. Current management of pancreatic carcinoma. Ann
Surg 1995;221:133–148.
Lillemoe KD, Kaushal S, Cameron JL, et al. Distal pancreatectomy:
indications and outcomes in 235 patients. Ann Surg
1999;229:693–700.
Loftus EV Jr, Olivares-Pakzad BA, Batts KP, et al. Intraductal papil-
lary-mucinous tumors of the pancreas: clinicopathologic features, outcome, and nomenclature. Members of the Pancreas
Clinic, and Pancreatic Surgeons of Mayo Clinic. Gastroenterol-
ogy 1996;110:1909–1918.
Mannell A, van Heerden JA, Weiland LH, et al. Factors influencing
survival after resection or ductal adenocarcinoma of the pancreas. Ann Surg 1986;203:403–407.
Martin I, Hammond P, Scott J, et al. Cystic tumours of the pancreas.
Br J Surg 1998;85:1484–1486.
Neoptolemos JP, Kerr DJ. Adjuvant therapy for pancreatic cancer. Br
J Surg 1995;82:1012–1014.
Pfau PR, Chak A. Endoscopic ultrasonography. Endoscopy 2002;34:
21–28.
Pitt HA. Curative treatment for pancreatic neoplasms. Standard
resection. Surg Clin North Am 1995;75:891–904.
Sarr MG, Cameron JL. Surgical management of unresectable carci-
noma of the pancreas. Surgery 1982;91:123–133.
Traverso LW, Longmire WP Jr. Preservation of the pylorus in pan-
creaticoduodenectomy. Surg Gynecol Obstet 1978;146:959–962.
Warshaw AL, Fernandez-del Castillo C. Pancreatic carcinoma. N
Engl J Med 1992;326:455–465.
Zerbi A, Balzano G, Patuzzo R, et al. Comparison between pylorus-
preserving and Whipple pancreatoduodenectomy. Br J Surg
1995;82:975–979.
132 ...........................................................................................................................................................
Three components comprise the neuroendocrine system:
the endocrine cells; the enteric nervous system (ENS); and
the extrinsic nervous system, including the peptidergic
components of the parasympathetic and sympathetic nervous systems.
ENDOCRINE CELLS
Endocrine cells are scattered throughout the mucosal
lining of the gut and are found in clusters only in the islet
cells of Langerhans in the pancreas. Some—like the
gastrin-secreting G cell of the antrum (Figure 5.2)—are of
the open type, having apical microvilli that reach the
lumen. Most are of the closed type, meaning they have
no microvilli and do not reach the lumen. They synthesize the peptides in the rough endoplasmic reticulum,
package them in granules, and transport them to the cell
membrane for exocytotic release into the interstitial
fluid. From there, the peptides diffuse either directly to
their target site (paracrine) or enter capillaries to be
carried by the blood to their target organ (endocrine).
Endocrine cells are stimulated to synthesize and/or release
their secretory peptides, usually by activation of receptormediated, G-protein-coupled signaling mechanisms. The
5
Gastrointestinal Peptides and Peptide-
Secreting Tumors (Apudomas)
NEUROENDOCRINE DESIGN OF THE GASTROINTESTINAL TRACT
exocytosis process has been studied extensively in the beta
cell of the pancreas. When the beta cell is stimulated (e.g.,
by glucose), its membrane depolarizes due to the closing
of ATP-sensitive potassium-ion (K
+
) channels. This, in
turn, leads to the opening of voltage-dependent calcium
channels, resulting in increased concentration of cytosolic
Ca
++
and insulin release. The same or similar mechanism
likely operates in the secretory process of all endocrine
cells.
ENTERIC NERVOUS SYSTEM
The enteric nervous system (ENS) is vast, comprising as
many nerve cells as the spinal cord. The term ENS is used
to describe the intrinsic innervation not only of the intestine but also of the esophagus, stomach, and pancreas. It
is made up of cell bodies, usually located in ganglia, and
of neural processes or axons that form the plexus. Within
the hollow gastrointestinal tract, the ganglia are arranged
in two groups: the submucosal ganglia and the myenteric
ganglia between the circular and longitudinal muscle
layers (Figure 5.3). The nerve processes of these two
systems of ganglia produce the submucosal and myenteric
plexus, respectively.
Complex neurohumoral interactions regulate the functions of the gastrointestinal tract.
These functions include secretion, motility, absorption, sensation, mucosal proliferation,
mucosal defense, immune regulation, and inflammatory response (Table 5.1). They are
mediated by peptides secreted from endocrine cells and nerves in the gastrointestinal tract
(Figure 5.1).
Gastrointestinal peptides become clinically significant in several pathological states, most
importantly when they are oversecreted by tumors arising from the cells that produce them.
Growing evidence also indicates that abnormalities in the secretion and distribution of gastrointestinal peptides underlie several motility disorders. As described later, these peptides
are important in clinical practice because they are used in the diagnosis as well as in the
therapy of disease states.
TABLE 5.1. Examples of Gastrointestinal Peptide Regulation of Function
Function Action Peptide(s)
Exocrine secretion
Gastric Stimulation Gastrin, GRP, PACAP
Inhibition Somatostatin
Pancreatic Stimulation CCK, secretin, VIP
Inhibition Somatostatin
Intestinal Stimulation VIP
Inhibition Somatostatin
Endocrine secretion Stimulation GRP (bombesin)
Inhibition Somatostatin
Motility Stimulation CCK, gastrin, motilin, neurotensin
Inhibition Somatostatin, VIP, PYY
Absorption Stimulation —
Inhibition Somatostatin, GIP
Sensation Stimulation Substance P, CGRP
Inhibition Somatostatin
Mucosal proliferation Stimulation Gastrin, CCK, enteroglucagon
Inhibition Somatostatin
Mucosal defense Stimulation CGRP, EGF, TGF-b, IFN-g
Inhibition —
Immune/inflammatory regulation Stimulation Substance P, cytokines (TNF, IL-1, IL-6, IL-8)
Inhibition ?
Inflammatory response Stimulation CGRP, substance P, cytokines
Inhibition Somatostatin
Food intake Stimulation —
Inhibition CCK, NPY
Abbreviations: CCK, cholecystokinin; CGRP, calcitonin gene-related peptide; EGF, epidermal growth factor; GIP, gastric
inhibitory peptide; GRP, gastrin-releasing peptide; IFN-g, interferon-gamma; IL-1, interleukin-1; IL-6, interleukin-6; IL-8,
interleukin-8; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase-activating polypeptide; PYY, peptide YY; TGF-b,
transforming growth factor-beta; TNF, tumor necrosis factor; VIP, vasoactive intestinal polypeptide.
FIGURE 5.1. Distribution of endocrine cells and peptidergic neurons in the gastrointestinal tract.
Abbreviations: CCK, cholecystokinin; CGRP, calcitonin gene-related peptide; GIP, gastric inhibitory
polypeptide; GRP, gastrin-releasing peptide; PYY, peptide YY; VIP, vasoactive intestinal polypeptide.
N euroendocrine D esign of the G astrointestinal Tract ..................................................................... 133
FIGURE 5.2. The gastrin-secreting G cell of the antrum is an
open-type endocrine cell with luminal microvilli. Gastrin is
secreted through the basal lateral membrane into capillaries.
Most of the ENS neurons are peptidergic, that is, they
synthesize peptides in their cell bodies, transport them
along their axons, and release them at the nerve terminals,
whence the peptides diffuse to bind to receptors on the
target cells to effect a response. Figure 5.4 depicts an
enteric neuron to demonstrate the life cycle of a neuropeptide, a peptide released by a neuron. Immunohistochemical techniques have facilitated the identification and
mapping of the enteric neurons.
The neuropeptides of the ENS serve as important
chemical messengers to regulate gastrointestinal function.
FIGURE 5.4. Life cycle of a neuropeptide. Peptidergic neurons
synthesize neuropeptides in their cell bodies and transport them
down the axons to be released at nerve terminals in close proximity to receptors on muscle, neural, and epithelial cells. Binding
of the neuropeptide to its receptor stimulates the production of
intracellular signals that eventuate in secretion or motility. Neuropeptidases at the external membrane of cells are strategically
placed to degrade neuropeptides. This degrading mechanism,
combined with internalization of the peptide receptor complex,
terminates the action of the neuropeptide.
FIGURE 5.3. The enteric nervous system is composed of submucosal and myenteric ganglia connected
by a network of neurons. (Adapted from Debas HT, Mulvihill SJ. Neuroendocrine design of the gut.
Am J Surg 1991;161:244.)
134 ............................................. Gastrointestinal P eptides and Peptide-Secreting T umors (Apudomas)
A partial summary of the nonpeptide and peptide chemical messengers in the gastrointestinal tract is given in
Table 5.2.
EXTRINSIC NERVOUS SYSTEM
The extrinsic innervation of the gastrointestinal tract
derives mostly from the sympathetic and parasympathetic
nervous systems. The sympathetic nervous system is distributed via the paravertebral ganglia and the greater and
lesser splanchnic ganglia. Sympathetic innervation reaches
target organs along the adventitia of arteries and arterioles. The parasympathetic system consists of the vagus,
which supplies all the organs derived from the foregut and
midgut and the lumbosacral outflow, which supplies the
structures derived from the hindgut.
These details have been well understood for a long
time. In recent years, however—thanks to immunohistochemical and anterograde and retrograde tracing techniques—it has been established that the sympathetic and
parasympathetic systems are not only adrenergic and
cholinergic, respectively, but also peptidergic, that is, they
contain neuropeptides. In addition, it has been demonstrated that the sensory innervation of the gastrointestinal
TABLE 5.2. Neurotransmitters of the Gastric Inhibitory Tract
Nonpeptides
Acetylcholine (ACh)
g-aminobutyric acid (GABA)
Nitric oxide (NO)
Noradrenaline
Serotonin
Peptides
Calcitonin gene-related peptide (CGRP)
Cholecystokinin (CCK)
Dynorphin
Enkephalin
Galanin
Gene-releasing peptide (GRP)
Neuropeptide Y (NPY)
Somatostatin (SS)
Tachykinins
Vasoactive intestinal polypeptide (VIP)
tract is mediated through unmyelinated C-fibers that predominantly contain substance P and CGRP.
The functional integration of peptidergic innervation is diagrammed in Figure 5.5. The role of sensory
innervation in reflex control of the gut is shown in Figure
5.6.
FIGURE 5.5. Functional integration of peptidergic innervation. Preganglionic neurons from the vagus
or spinal cord activate enteric ganglia through the release of acetylcholine. (A) The postganglionic
neurons then act on target cells (e.g., endocrine or muscle cells), again through cholinergic neurotransmission. A different type of integration involves the release of a peptide from an endocrine cell.
(B) The peptide then acts on intrinsic muscurinic neurons to activate exocrine secretion (e.g., pancreatic secretion). (C) The third type of integration involves preganglionic cholinergic neurons acting on
postganglionic peptidergic neurons to release peptides, which then act on target cells (e.g., release of
gastrin by gastrin-releasing peptide). (D) The final type of integration is exemplified by the release of
histamine in stimulation of acid secretion. The peptide gastrin or cholinergic neurons act on ECL cells
to release histamine.
N euroendocrine D esign of the G astrointestinal Tract ..................................................................... 135
(Continued)
FIGURE 5.5. Continued
FIGURE 5.6. Role of sensory innervation in reflex control of the
gut. Stretch receptors in the gut wall are stimulated by distention. The response is transmitted through afferent C-fibers to
the dorsal root ganglia and then to the posterior horn. Spinal
neurons then carry the message to the vagal nucleus in the
medulla oblongata. Efferent vagal neurons carry the response to
the intestinal wall, which, through cholinergic transmission, activates the release of vasoactive intestinal polypeptide (VIP) from
intrinsic peptidergic neurons. The VIP then acts to relax the
enteric smooth muscle. Abbreviation: ACh, acetylcholine.
CLASSIFICATION OF GASTROINTESTINAL PEPTIDES
Gastrointestinal peptides may be classified either by chemical structure or by mode of action. Structurally, they have
been classified into several families, which share structural
similarities (e.g., the CCK/gastrin family; the secretin
family [secretin, VIP, PHI]; and the PP family [PP, NPY,
136 ............................................. Gastrointestinal P eptides and Peptide-Secreting T umors (Apudomas)
PYY]). A classification of gastrointestinal peptides based
on their mode of action is given in Table 5.3.
Endocrine peptides are secreted into the circulation
and transported in the bloodstream to reach their target
organ or cell. Paracrine agents are secreted into the inter-
TABLE 5.3. Classification of Gastrointestinal Peptides
Endocrine
Cholecystokinin (CCK)
Gastric inhibitory peptide (GIP)
Gastrin
Motilin
Neurotensin
Pancreatic polypeptide
Peptide YY
Secretin
Somatostatin
Paracrine
Somatostatin
Vasoactive intestinal polypeptide (VIP)
Neurocrine
Calcitonin gene-related peptide (CGRP)
Cholecystokinin (CCK)
Galanin
Gastrin-releasing peptide (GRP)
Neuropeptide Y
Opioid peptides
Somatostatin
Substance P
Vasoactive intestinal polypeptide (VIP)
stitial fluid and reach their target site by diffusion over distances that can be measured in nanometers or millimeters.
Neurocrine agents are released at nerve endings and
usually have to cross only a short synaptic gap to reach the
target cell. This classification is imperfect because several
peptides have more than one mode of action. For example,
CCK acts as both a hormone and a neuropeptide, while
somatostatin acts in all three capacities as an endocrine,
paracrine, and neurocrine agent. Only gastrin and secretin
appear to act solely as endocrine peptides within the gastrointestinal tract.
GASTRIN
The existence of gastrin was hypothesized by Edkins in
1905, when he demonstrated that antral extract stimulated
acid secretion in the cat.
1
Many attributed the observation
to contaminant histamine until 1938, when Komorov
prepared histamine-free extract that retained acidstimulatory effect.
porcine gastrin and characterized its amino acid
sequence.
3
2
In 1964, Gregory and Tracy purified
Distribution
Gastrin is produced by G cells, which are located primarily in the mid-layer of the antral mucosa. These cells are
also present in the duodenum, particularly in the first
portion. Gastrin, present in the pancreas of the fetus, is not
in the adult pancreas. Gastrin-like immunoreactivity is
also found in the brain.
Structure and Synthesis
The gene that encodes gastrin has been isolated and
characterized from porcine antrum and from a human
genomic DNA library, as well as from a human antral
cDNA library. A single gene produces a single progastrin
sequence from which all molecular forms of gastrin are
derived by post-translational processing. The human gene,
located on chromosome 17, is about 4100 base pairs long.
Gastrin cDNA contains 620 nucleotides, including an
open reading frame of 312 nucleotides that encode preprogastrin. Gastrin gene expression in the antrum is regulated by luminal contents and pH in parallel with gastrin
release. Post-translational processing of gastrin produces
the various molecular forms and involves several cleavage
steps and C-terminal amidation (Figure 5.7). Human preprogastrin consists of 101 amino acids. From this, an 80amino acid progastrin is cleaved (preprogastrin 22–101).
Progastrin is processed further in the Golgi complex and
secretory granules into mature gastrin, G-17 and G-34.
These peptides are amidated at the C-terminus. The final
step in producting biologically active gastrin is deamidation of the C-terminal phenylalanine residue. About half
of the gastrins isolated from the human antrum and duodenum are sulfated.
FIGURE 5.7. Post-translational processing of gastrin (preprogastrin). A number of molecular forms of
gastrin are processed from the human preprogastrin. These molecular forms (e.g., big gastrin, G17)
have C-terminal amide extension, which is removed by the action of amidase to release the active
peptide.
C lassification of Gastrointestinal P eptides ...................................................................................... 137
The most abundant form of gastrin in the blood is G34, comprising two-thirds of circulating gastrin in the
fasting state and half in the postprandial state. The
remainder is primarily G-17, with small amounts of G-14
and component I. Circulating G-34 and G-17 have similar
potency for stimulating acid secretion. The C-terminal
tetrapeptide retains acid-stimulating property but is 25
times less potent than G-17.
Release of Gastrin
Gastrin is released by peptides, amino acids, and calcium
in the antral lumen. It is also released by gastric distension,
which activates vasovagal nervous reflexes. Other releasers
of gastrin include catecholamines and gastrin-releasing
peptide (bombesin). Inhibition of gastrin is caused by
antral acidification, which acts by releasing somatostatin from delta cells in close proximity to G cells. While
sham feeding does release gastrin, the more dominant
action of the vagus on gastrin release is inhibitory. Thus,
following all types of vagotomy, hypergastrinemia
develops.
Receptors and Postreceptor Signaling
The gastrin receptor has been cloned from canine parietal
cells. It is also known as the CCK-B receptor because of its
close structural relationship to CCK-A receptor, with
which it shares 50% amino acid identity. CCK-B receptors,
like the CCK-A receptors, have a seven membranespanning region and belong to the class of G proteincoupled receptors. When the receptor is activated by
gastrin binding, phospholipase C is stimulated, resulting
in the production of diacylglycerol and inositol 1,4,5
triphosphate in the cytoplasm of the target cell. This, in
turn, leads to increased intracellular calcium concentration and activation of protein kinase C. The gastrin CCKB receptor does not distinguish between gastrin and CCK,
or between sulfated or unsulfated gastrin and CCK. In
contrast, gastrin does not bind or binds little to the CCKA receptor. The receptor and postreceptor mechanisms are
diagrammed in Figure 5.8.
Gastrin CCK-B receptors are found on parietal cells,
ECL cells, gastric oxyntic mucosal proliferative cells (stem
cells), the lower esophageal sphincter muscle, gastric antral
smooth muscle, and a subpopulation of pancreatic acinar
cells. The gastrin CCK-B receptor is also found throughout the brain.
Biological Actions of Gastrin
The major biological actions of gastrin include the following items:
1. Acid secretion. Gastrin mediates most of the acid
response to a meal during the gastric phase of acid secretion. In the dog, acid response to a meal can be prevented
by pretreatment with monoclonal antibody to gastrin.
Gastrin acts on CCK-B receptors on the ECL cell to release
histamine, which then stimulates the parietal cell by acting
on the histamine H
the parietal cell, but the dominant mechanism for its acid
secretory function is through activation of the ECL cell in
the gastric oxyntic mucosa.
2. Trophic action. Gastrin is the primary growth regulator of the oxyntic gland mucosa. Hypergastrinemic
states cause growth of the oxyntic mucosa and parietal cell
hyperplasia. Gastrin also acts on the crypt cells in the duo-
-receptor. Gastrin also acts directly on
2
FIGURE 5.8. Receptors and postreceptor processes of gastrin. The gastrin receptor is a typical sevenmembrane spanning, G-protein–coupled receptor.
138 ............................................. Gastrointestinal P eptides and Peptide-Secreting T umors (Apudomas)
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