1 CURE: Digestive Diseases Research Center, Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles 90073; 2 Digestive Diseases Division, UCLA School of Medicine, Los Angeles, California 90024; and 3 Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1450 Budapest, Hungary
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ABSTRACT |
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Only one secretin receptor has been cloned and its properties characterized in native and transfected cells. To test the hypothesis that stimulatory and inhibitory effects of secretin are mediated by different secretin receptor subtypes, pancreatic and gastric secretory responses to secretin and secretin-Gly were determined in rats. Pancreatic fluid secretion was increased equipotently by secretin and secretin-Gly, but secretin was markedly more potent for inhibition of basal and gastrin-induced acid secretion. In Chinese hamster ovary cells stably transfected with the rat secretin receptor, secretin and secretin-Gly equipotently displaced 125I-labeled secretin (IC50 values 5.3 ± 0.5 and 6.4 ± 0.6 nM, respectively). Secretin, but not secretin-Gly, caused release of somatostatin from rat gastric mucosal D cells. Thus the equipotent actions of secretin and secretin-Gly on pancreatic secretion appear to result from equal binding and activation of the pancreatic secretin receptor. Conversely, secretin more potently inhibited gastric acid secretion in vivo, and only secretin released somatostatin from D cells in vitro. These results support the existence of a secretin receptor subtype mediating inhibition of gastric acid secretion that is distinct from the previously characterized pancreatic secretin receptor.
posttranslational processing; receptor specificity; D cells; somatostatin
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INTRODUCTION |
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MANY REGULATORY PEPTIDES
EXIST in multiple molecular forms generated by different degrees
of posttranslational processing in their cell of synthesis. This
differential processing can regulate the expression of biological
activity for a peptide if receptor subtypes exist that select among the
processed forms. One example is the family of PYY and NPY peptides and
receptor subtypes: PYY-(1-36) and the more fully
processed form PYY-(3-36) have different spectra of
binding to their receptor subtypes (13). Preliminary
evidence (38) suggests that two molecular forms of
secretin exist in tissue and plasma: fully processed secretin
[secretin-(1-27)-amide] and its immediate
precursor, secretin-Gly. We recently reported (26) that
COOH-terminally extended forms of secretin produced during
posttranslational processing of preprosecretin were equipotent with
fully processed secretin for stimulating pancreatic secretion. This was
surprising because it suggests that the -carboxyl amide group at the
COOH terminus of secretin is not a required structural element for
efficient binding and activation of the secretin receptor that
stimulates pancreatic fluid secretion. Only one secretin receptor has
been cloned and characterized by molecular and pharmacological approaches (28), and this receptor is thought to mediate
the stimulatory effect of secretin on pancreatic fluid and bicarbonate secretion. However, the relative potencies of COOH-terminally extended
secretin forms for binding and activation of this receptor have not
been determined.
Secretin has a wide range of actions, including stimulatory effects on pancreatic and biliary secretion, regulatory peptide release, cardiac and neural activity, and other functions; conversely, secretin has inhibitory effects on gastric acid secretion and motility (28, 33). In rats, secretin is a potent inhibitor of gastric acid secretion (25). Several observations indicate that the inhibitory action of secretin on gastric acid secretion is mediated by local release of somatostatin from oxyntic gland area D cells (25). Secretin has been reported to stimulate somatostatin secretion by cultured human antral D cells (3), suggesting that D cells may be one target that bears the inhibitory secretin receptor. The ability of COOH-terminally extended forms of secretin to inhibit gastric acid secretion has not been previously examined.
Although the stimulatory and inhibitory effects of secretin could be exerted through one receptor, there are precedents for receptor subtypes that differentially mediate stimulatory and inhibitory actions of other agonists (34). We examined the relative potencies of secretin and secretin-Gly on pancreatic secretion and gastric acid secretion to test the hypothesis that stimulatory and inhibitory actions of secretin are mediated through different secretin receptors. As a further test of this hypothesis, we compared the relative potencies of secretin and secretin-Gly for binding to the rat pancreatic secretin receptor subtype in stably transfected Chinese hamster ovary (CHO) cells and release of somatostatin from gastric mucosal D cells in vitro. These studies revealed distinct differences in the patterns of pancreatic and gastric secretory effects and in vitro actions of secretin and secretin-Gly, suggesting the existence of a second secretin receptor subtype.
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MATERIALS AND METHODS |
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Peptides.
Synthetic canine and rat secretins with COOH-terminal -carboxyl
Val-amide [secretin-(1-27)-amide] or Val-Gly
[secretin-(1-27)-Gly] were synthesized by the UCLA
Peptide Synthesis Core Facility under the direction of one of the
authors (J. R. Reeve, Jr.). The peptides were purified by HPLC and
evaluated by amino acid analysis, microsequencing, mass spectroscopy,
and analytical reverse-phase HPLC. The details of these syntheses and
purifications have been reported (26). Secretin peptides
were weighed to the nearest microgram and dissolved in 2% (vol/vol)
acetic acid. Aliquots of these solutions were stored frozen at
70°C; each aliquot was thawed only once, and any remainder was
discarded after preparation of daily working solutions. Gastrin-17 was
dissolved in 50 mM NH4OH containing 1% (wt/vol) BSA (RIA
grade, Sigma Chemical, St. Louis, MO), divided into aliquots, and
stored in the same manner as for secretin stocks. The exact peptide
concentrations in secretin stock solutions were determined by
quantitative amino acid analysis, and the same stock solutions were
used for all experiments reported. For administration, stocks were
thawed and diluted to appropriate concentrations in 0.15 M NaCl
containing 1% BSA. The diluted solutions were kept on ice until use
within a few hours. Peptide solutions were administered using syringe
pumps mounted with plastic disposable syringes and polyethylene tubing.
Animal models. Male Sprague-Dawley rats (250-320 g) were purchased from Sasco (Omaha, NE) and housed in an American Association for Accreditation of Laboratory Animal Care-approved facility. Rats were kept in the animal facility for at least 7 days before use and were maintained under controlled temperature and humidity on a standard rodent diet and an equal light-dark cycle.
For pancreatic studies, all animals were deprived of food for 24 h. Anesthesia was induced by administration of urethan (1.25 g/kg, given as divided im and ip injections). A jugular vein catheter (PE-50) was inserted, and 0.15 M NaCl containing 1% (wt/vol) BSA was given intravenously at 1.0 ml/h throughout the experiment. A midline celiotomy was performed, followed by ligation of the pylorus, ligation of the biliary duct proximal to its investment by pancreatic tissue, and insertion of a catheter (PE-50) into the distal bile-pancreatic duct for collection of pure pancreatic juice. Core body temperature was monitored using a rectal thermocouple and maintained at 35-37°C with a heating pad and heat lamp. For gastric studies, rats were fasted for 24 h and then prepared with gastric cannulas and venous catheters using aseptic surgical techniques similar to those described previously (31). Anesthesia was induced with pentobarbital sodium (35-50 mg/kg ip). A polyethylene catheter (PE-50) was inserted into the jugular vein, tunneled subcutaneously to exit in the midscapular region, filled with saline containing 10 U/ml heparin, and capped. A stainless steel cannula was inserted into the forestomach and ligated in place with a purse-string suture. The cannula was brought through the abdominal wall to the left of the midline and capped, and the abdominal incision was closed in two layers. After awakening from anesthesia, the rats were allowed free access to food and water. Rats were allowed to recover for at least 5 days before experiments began, and at least 4 days elapsed between experiments. After each experiment, the rats were returned to individual cages and given free access to food and water. All studies reported were performed on animals that showed normal weight gain and appeared healthy.Design of pancreatic and gastric secretory studies.
After a 60-min stabilization period, pancreatic juice was collected
during sequential 30-min periods. After two basal collections, canine
secretin (n = 12 rats) or secretin-Gly
(n = 16 rats) was administered in ascending doses of 1, 3, 10, 30, 100, 300, and 1,000 pmol · kg1 · h
1; each dose
was given for 30 min. The volume of pancreatic juice was determined
gravimetrically using preweighed collection tubes.
Characterization of secretin receptor binding.
Binding experiments were performed with a CHO cell line expressing the
transfected rat secretion receptor (rSecR-1, a gift from Dr. Laurence
J. Miller, Mayo Clinic, Rochester, MN). Cells were cultured in
poly-L-lysine-coated 24-well plates with DME-F-12 medium
containing 10% fetal calf serum. Cells were grown to a final density
of 1-2 × 106 cells/well. They were rinsed twice
with PBS (150 mM NaCl, 10 mM sodium and potassium phosphate, pH 7.2),
and 1 ml of cell binding buffer [DME-F-12 medium, 20 mM HEPES, pH 7.4, 0.1% (wt/vol) bacitracin, 0.2% (wt/vol) BSA] was then added into
each well. Binding assays were started by adding
125I-secretin-(1-27)-amide (rat peptide,
20 pM, ~2,000 Ci/mmol) in the presence of increasing concentrations
of unlabeled rat peptides as indicated. The radiolabeled tracer was
prepared, purified, and stored as described previously
(26). After 1-h incubation at 37°C, cells were washed
twice with ice-cold PBS and solubilized in 1 ml of 1% (vol/vol) Triton
X-100 in PBS. Radioactivities of bound (cell lysate) and free (medium)
fractions were counted, and these values were used to calculate
specific binding, expressed as a percentage of maximal binding (with
tracer alone). Total binding in these experiments was in the range of
4,000-5,000 cpm per well, whereas nonspecific binding in the
presence of 106 M secretin was 200-300 cpm. Kinetic
constants were calculated by nonlinear regression curve fitting using a
one-site model (Prism 3.0, GraphPad, San Diego, CA).
Somatostatin release from gastric mucosal endocrine cells.
Rat gastric endocrine cells were isolated by a combination of
elutriation and density gradient centrifugation as described previously
(37). The proportion of immunostained D cells in this
preparation ranges from 12 to 30%. Freshly isolated endocrine cells
were rinsed by gentle centrifugation in growth medium containing DME-F-12 supplemented with 2 mg/ml BSA, 2.5% FCS, 100 µM
hydrocortisone, 1% penicillin-streptomycin, 5 mg/ml insulin, 5 mg/ml
transferrin, and 5 µg/ml sodium selenite. Aliquots of the washed cell
suspension were placed on glass coverslips precoated with Cell-Tak and
incubated at 37°C for 45 min, allowing cell attachment to the
coverslips. Then 0.8 ml of growth medium was added to the coverslips in
six-well plates. Somatostatin release was determined after 48-h culture by incubating endocrine cells in Cell-Tak-precoated coverslips in
six-well plates. Growth medium was replaced 3 h before the release
experiments. After cells were incubated with graded concentrations of
rat secretin and secretin-Gly for 2 h, the test medium was harvested, centrifuged, and stored at 20°C for somatostatin assay. Radioimmunoassay of somatostatin was performed with anti-somatostatin antiserum (AB 8401) as described previously (36). In each
experiment, somatostatin secretion was calculated as the average of six
wells exposed to each peptide concentration.
Calculations and statistical analysis. All data are presented as group means ± SE, with n as the number of rats in each group. Statistical significance of changes in secretory outputs was assessed both within and across groups. One-way repeated-measures analysis of variance was followed by appropriate repeated-measures individual comparisons within groups. One-way analysis of variance or Student's t-test was used for comparisons across groups; appropriate corrections were made for multiple comparisons. Statistically significant changes were accepted at P < 0.05.
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RESULTS |
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Stimulation of pancreatic secretion.
Secretin and secretin-Gly caused indistinguishable patterns of
pancreatic fluid secretion over the range of doses administered (Fig.
1). Bicarbonate concentration and output
also showed similar increases in response to both secretin forms, and
rat secretin and secretin-Gly produced identical results (data not
shown).
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Inhibition of acid secretion.
The patterns of gastric acid secretion during basal and
gastrin-stimulated conditions were stable and reproducible. This is illustrated in Fig. 2, which shows the
time course of basal and gastrin-induced acid output in control
studies. Unstimulated acid secretion did not vary over the 4-h period
of observation. During intravenous infusion of 1.25 nmol · kg1 · h
1 gastrin-17,
acid output increased about fourfold compared with basal output and was
stable for at least 3 h. These data were used for comparison to
patterns of acid secretion in rats treated with secretin and
secretin-Gly during basal (Fig. 3) and
gastrin-stimulated (Fig. 4) conditions.
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Secretin receptor binding.
As seen in Fig. 5, secretin and
secretin-Gly were equipotent for displacing 125I-secretin
from CHO cells bearing the stably transfected rat secretin receptor.
The dissociation constant values calculated for the two peptides were
5.3 ± 0.5 and 6.4 ± 0.6 nM.
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Somatostatin release from gastric mucosal D cells.
Figure 6 demonstrates the effects of
secretin and secretin-Gly on somatostatin release from a partially
purified preparation of rat gastric mucosal endocrine cells. In
contrast to their similar patterns of displacement of radiolabeled
secretin from the rat secretin receptor, there were striking
differences in D cell somatostatin release by the two peptides.
Secretin increased somatostatin release by nearly threefold at a
concentration of 107 M, whereas secretin-Gly was
ineffective at concentrations up to 10
6 M (Fig. 6).
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DISCUSSION |
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The results of these studies can be summarized as follows: secretin and secretin-Gly were equipotent ligands for binding to the transfected rat pancreatic secretin receptor and for stimulating pancreatic fluid secretion in vivo, and secretin was significantly more potent than secretin-Gly for releasing somatostatin from gastric mucosal D cells in vitro and for inhibiting basal and gastrin-stimulated acid secretion in vivo. The most plausible explanation for these findings is the existence of secretin receptor subtypes. The subtype that stimulates pancreatic fluid secretion is likely to be the previously described pancreatic receptor (29), which we demonstrate here as recognizing secretin and secretin-Gly equally. A second receptor is preferentially activated by secretin and causes inhibition of gastric acid secretion. Other explanations for the different actions of secretin and secretin-Gly on gastric secretion, such as differences in metabolism of the two peptides or effects on non-secretin receptors, are unlikely.
We were not able to measure plasma levels of secretin-Gly to ensure that similar doses of secretin and secretin-Gly resulted in similar circulating concentrations. However, several points suggest that differences in metabolism of secretin and secretin-Gly probably do not account for the observed effects on pancreatic and gastric function. Fully processed and COOH-terminally extended secretins have equal or greater potency for stimulating pancreatic secretion in vivo (26). In contrast, secretin inhibited but secretin-Gly stimulated basal acid output, and secretin was distinctly more effective in inhibiting gastrin-induced acid secretion. These observations would require organ-specific differences in inactivation of the two forms of secretin if peptide degradation, rather than activation of different secretin receptor subtypes, was responsible for the two patterns of activity. A more plausible explanation for these disparate actions of fully processed and COOH-terminally extended secretin is that two receptors with different patterns of recognition are involved in stimulation of pancreatic fluid secretion on one hand and inhibition of gastric acid secretion on the other.
It is also highly unlikely that the actions of fully processed and COOH-terminally extended secretin were mediated by nonspecific actions on other receptors, such as those for vasoactive intestinal polypeptide (VIP) or pituitary adenylate cyclase-activating peptide (PACAP). A specific secretin receptor has been cloned from a rat pancreatic cDNA library (14, 29). This secretin receptor is localized to pancreatic duct and acinar cells (30) and almost certainly mediates the direct stimulatory effects of secretin on bicarbonate secretion by duct cells and enzyme secretion by acinar cells. Neither VIP nor PACAP is a potent stimulant of pancreatic secretion in the rat (1, 16). The crucial questions for the hypothetical existence of a different secretin receptor that mediates inhibition of gastric acid secretion involve the characteristics of secretin-induced inhibition of acid secretion and the localization (and thus the potential mechanism of action) of such a receptor. In rats, secretin is a potent inhibitor of gastric acid secretion under certain conditions (25); VIP does not inhibit acid secretion in rats (18), and PACAP is a weak inhibitor that acts indirectly (17, 18).
The mechanisms by which secretin inhibits gastric acid secretion appear
to be indirect via release of somatostatin and prostaglandins. The
effects of secretin on acid secretion are blocked by
immunoneutralization of somatostatin and by inhibition of prostaglandin
synthesis (25). Secretin increases gastric venous effluent
levels of somatostatin (5-7, 24, 35) and
prostaglandin E2 (7). These observations indicate that the inhibitory action of secretin on gastric acid secretion is mediated by local release of somatostatin by gastric mucosal D cells and prostaglandin E2 by unknown cells.
Secretin has been reported to stimulate somatostatin secretion by
cultured human antral D cells (3), suggesting that D cells
may be one target that bears the inhibitory secretin receptor. Our
finding that secretinbut not secretin-Gly
induced somatostatin
release from partially purified rat mucosal D cells supports this
hypothesis. However, we observed that secretin-Gly was weaker but not
completely ineffective for inhibition of gastric acid secretion. This
suggests that other inhibitory mechanisms such as prostaglandin
generation may be activated by both molecular forms of secretin.
With Northern blot analysis of mRNA, the single rat secretin receptor that has been cloned to date (14, 29) has been localized to several tissues including the stomach (14). More precise definition of the cell types bearing this receptor is not currently available. The existence of secretin receptors on chief cells (23), fundic or antral D cells (3, 5-7, 24, 35), mucus-secreting cells (15), and forestomach smooth muscle cells (27) in rats is suggested by experimental data showing direct actions of secretin on the isolated stomach, mucosa, or cell populations in vitro. All of these experimental results were obtained using only fully processed secretin, because COOH-terminally extended secretin forms have not been available for characterization of their bioactivities.
Structure-activity relationships for binding and activation of the
secretin receptor have been investigated using the cloned pancreatic
receptor subtype. When this receptor or chimeric receptors composed of
portions of the secretin, VIP, and glucagon receptors are studied,
deletion of the NH2-terminal histidyl residue of secretin
reduces binding and activation by 1,000-fold (32), indicating a critically important role of the NH2-terminal
structure of secretin for binding and activation. For the pancreatic
secretin receptor, the COOH-terminal region of secretin also appears to be involved in receptor recognition, although to a lesser degree; peptides with deletions of the COOH-terminal Val-amide or
Gly-Leu-Val-amide were only 10- and 50-fold less potent than intact
secretin-(1-27)-amide (12). Recognition
of the NH2-terminal histidyl residue of secretin by the
pancreatic secretin receptor subtype also appears to be sensitive to
addition of amino acid residues, at least as judged by the distinctly
lower in vivo bioactivity of an alternatively processed secretin form
with an NH2-terminal nonapeptide extension and
COOH-terminal amidation (2). In contrast, COOH-terminal extensions of secretin do not reduce its pancreatic secretory bioactivity in vivo (present results and Refs. 4, 9, 10, 26) or binding (present results) and functional activation
(19) of the pancreatic secretin receptor in vitro. The
secretin receptor that mediates inhibition of gastric acid secretion
appears to be very specific for the presence of an -carboxyl amide
group. We show here that addition of a COOH-terminal glycyl residue
markedly reduces the acid inhibitory potency of secretin, and in
unpublished studies we observed that the free acid form of secretin was
also clearly less potent for this action. The acid-inhibitory effect of
secretin is also affected by the NH2-terminal structure of the peptide, because secretin-(5-27) is ineffective
in blocking gastrin-induced acid secretion in rats (unpublished
observation). Finally, it has been shown that residues 8-15 of
secretin are important for the transfected pancreatic receptor to
distinguish secretin from PACAP (11), suggesting that this
region should also be evaluated for differences between the pancreatic
and acid-inhibitory secretin receptor subtypes.
The data presented here indicate that there are at least two secretin receptor subtypes with different selectivities for fully processed vs. COOH-terminally extended secretins. In addition, the equipotency of secretin and secretin-Gly for binding to the cloned and transfected rat pancreatic secretin receptor suggests that previously described COOH-terminally extended molecular forms of secretin may be of physiological importance. There are several possible mechanisms that could result in the existence of a secretin receptor subtype with different selectivities for secretin molecular forms. First, there could be two structurally different receptors produced by two different genes. In general, most families of receptor subtypes appear to be produced by this mechanism, and members of these families show a substantial degree of structural homology at the nucleotide and amino acid levels (8). The presence of multiple bands on Northern blot analysis of various tissues with a secretin receptor probe is indirect evidence that structurally related receptors might indeed exist (21). Second, there may be only a single secretin receptor gene product that undergoes differential mRNA splicing, posttranslational processing, or G protein coupling to result in tissue-specific differences in agonist selectivity. Different patterns of mRNA splicing can produce distinct functional differences in receptors, as exemplified by splice variants of the PACAP receptor (22). The degree of posttranslational processing of the secretin receptor has in fact been shown to alter patterns of secretin binding and activation (20). It is at least theoretically possible that this could also result in different agonist selectivity of the known secretin receptor. It is also theoretically possible that tissue-specific differences in G protein coupling could alter receptor selectivity for different molecular forms of secretin.
Receptor subtypes provide the potential to select among structurally related agonists that are produced by different genes (i.e., the CCK-A receptor selects between CCK and gastrin) or by posttranslational processing of a single gene product [i.e., the Y1 receptor selects between NPY/PYY-(1-36) and NPY/PYY-(3-36)]. Our preliminary characterization of the relative amounts of secretin molecular forms in rat intestine indicates that secretin-Gly is present in at least 50% of the amount of secretin (38). The ratio of the two forms may be regulated by physiological conditions (postnatal development, feeding, acid secretion). These considerations suggest that the existence of secretin receptor subtypes could be functionally significant for selecting between secretin and secretin-Gly for actions on pancreatic and gastric secretion, as well as other potential targets of secretin. The use of secretin and secretin-Gly as pharmacological probes should facilitate the identification of putative secretin receptor subtypes and their participation in gastrointestinal and other regulatory events mediated by secretin.
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ACKNOWLEDGEMENTS |
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The excellent technical assistance of Louis Bussjaeger and Peter Chew is gratefully acknowledged.
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FOOTNOTES |
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This research was supported by the CURE Digestive Diseases Research Center Grant DK-41301 and utilized the Peptide Biochemistry and Molecular Probes, Animal Model, and Antibody Center Cores. The research was also supported by the Medical Research Service of the Veterans Health Service.
Address for reprint requests and other correspondence: T. E. Solomon, Research Service (151), Bldg. 115, Rm. 111, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, CA 90073 (E-mail: solomont{at}ucla.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 4 May 2000; accepted in final form 21 August 2000.
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