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PubMed2005

Expression and spatial distribution of secretin and secretin receptor in human cerebellum.

The expression and spatial distribution of secretin and its receptor in human cerebellum were investigated by in situ hybridization and immunohistochemical techniques. Secretin mRNAs are found in Purkinje cells whereas secretin receptor transcripts are present in Purkinje cells and basket cells in the molecular cell layer. In addition, secretin-immunoreactivities are localized in both the soma and dendrites of Purkinje cells. These data are the first demonstration of the spatial distribution of secretin and its receptor in distinct neurons within the human cerebellum. The cellular localizations of this ligand-receptor pair are consistent with the proposed actions of secretin in the cerebellum of rodents and hence suggest that secretin also serves specific neural functions in the human cerebellum.

Cerebellum↗
PubMed1991

Synthesis of biologically active porcine secretin and [ITyr10] porcine secretin.

Porcine secretin, [Tyr10] secretin, and [Tyr13] secretin were synthesized by solid phase methodology and purified by stepwise gradient elution from a short reversed-phase column with ethanol and acetic acid as organic modifiers. [Tyr10] secretin and [Tyr13] secretin were iodinated by the chloramine-T method and nonmono-, and di-iodinated products separated and isolated by reversed-phase HPLC. Batch incubation analysis is isolated mouse pancreatic islets revealed that secretin and the [Tyr10] analogue were indistinguishable in their effect on the glucose-induced insulin release and cAMP accumulation. [Tyr13] secretin in contrast was significantly less potent in its effect on the glucose-induced insulin release.

Amino Acid Sequence↗
PubMed1995

Neuronal regulation of the release and action of secretin-releasing peptide and secretin.

The acid-stimulated release of secretin is mediated by a secretin-releasing peptide (SRP) in rats. In the present study we investigated to determine whether a neural mechanism(s) is involved in the regulation of release and action of SRP in anesthetized rats. A concentrated acid perfusate (CAP) containing SRP was obtained from donor rats. CAP administered to recipient rats significantly increased pancreatic flow volume (81.6 +/- 18.3%), bicarbonate output (188.7 +/- 15.6%), and plasma secretin level (from 0.9 +/- 0.2 to 4.4 +/- 0.5 pM). However, this effect was attenuated by CAP from donor rats pretreated with tetrodotoxin (TTX), propranolol, bilateral subdiaphragmatic vagotomy (BSV), or systemic and topical administration of capsaicin. In contrast, CAP from donor rats pretreated with phentolamine, atropine, or hexamethonium did not alter the increase in plasma secretin concentration and pancreatic secretion. Moreover, the action of CAP on secretin release was significantly inhibited in the recipient rats pretreated with TTX, BSV, and topical applications of capsaicin but was not suppressed in the recipient rats pretreated with atropine, hexamethonium, or propranolol. Furthermore, perivagal and duodenojejunal mucosal application of capsaicin abolished the pancreatic secretory response to secretin at 5 pmol.kg-1.h-1. In conclusion, the release and action of both SRP and secretin are mediated by a vagal afferent pathway. beta-Adrenergic receptors also play a significant role in the release of SRP.

Acids↗
PubMed1987

Influence of vasoactive intestinal peptide, secretin, and Ala4, Val5-secretin on the net movements of electrolytes, fluid, and mucus in the rat colon in vivo.

The effect of vasoactive intestinal peptide (VIP), secretin, and VIP-secretin (Ala4, Val5-secretin) on the net movements of sodium, potassium, fluid, and mucus was investigated in the rat colon perfused in vivo. Peptides (1-100 micrograms/kg.h) were infused intra-arterially. VIP influenced electrolyte and fluid movements at a threshold dose 10- to 100-fold lower than secretin, whereas the secretory efficacy was not significantly different. Replacing the NH2-terminal hexapeptide of secretin by that of VIP did not markedly alter the effect of secretin. Mucus output was stimulated weakly by all three peptides. The results indicate that the larger colonic secretory activity of VIP as compared to secretin is not primarily due to the difference in their NH2-terminal sequence but probably requires the intact molecule.

Animals↗
PubMed1982

Comparative effects of synthetic and natural secretin on pancreatic secretion and on secretin, insulin, and glucagon levels in man.

The effect of synthetic secretin (Roche) on exocrine pancreatic secretion and on secretin, insulin, and glucagon levels was determined and compared with that of pure natural porcine secretin (GIH, Karolinska Institutet, Stockholm) in 10 healthy volunteers. The two secretin preparations were found to be equipotent. Equipotency applies to pancreatic secretion and to secretin and insulin plasma levels, whereas the plasma levels of glucagon were not affected by either drug. It is concluded that this synthetic secretin preparation is suitable for clinical and research purposes.

Adult↗
PubMed1999

Demonstration of a direct interaction between residue 22 in the carboxyl-terminal half of secretin and the amino-terminal tail of the secretin receptor using photoaffinity labeling.

An understanding of the molecular basis of hormonal activation of receptors provides important insights for drug design. Toward this end, intrinsic photoaffinity labeling is a powerful tool to directly identify the ligand-binding domain. We have developed a new radioiodinatable agonist ligand of the secretin receptor that incorporates a photolabile p-benzoyl-L-phenylalanine (Bpa) into the position of Leu22 and have utilized this to identify the adjacent receptor domain. The rat [Tyr10,Bpa22]secretin-27 probe was a fully efficacious agonist, with a potency to stimulate cAMP accumulation by Chinese hamster ovary SecR cells similar to that of natural secretin (EC50 = 68 +/- 22 pM analogue and 95 +/- 25 pM secretin). It bound specifically and with high affinity (Ki = 5.0 +/- 1.1 nM) and covalently labeled the Mr = 57,000-62,000 secretin receptor. Cyanogen bromide cleavage of the receptor yielded a major labeled fragment of apparent Mr = 19,000 that shifted to Mr = 9,000 after deglycosylation. This was most consistent with either of two glycosylated domains within the amino-terminal tail of the receptor. Immunoprecipitation with antibody directed to epitope tags incorporated into each of the candidate domains established that the fragment at the amino terminus of the receptor was the site of labeling. This was further localized to the amino-terminal 30 residues of the receptor by additional proteolysis of this fragment with endoproteinase Lys-C. This provides the first direct demonstration of a contact between a secretin-like agonist and its receptor and will contribute a useful constraint to the modeling of this interaction.

Amino Acid Sequence↗
PubMed2000

Direct measurement of pancreatic enzymes after stimulation with secretin versus secretin plus cholecystokinin.

BACKGROUND: Direct measurement of pancreatic enzymes after administration of pancreatic secretagogues is the gold standard in the assessment of exocrine pancreatic function. Recent experience at the authors' institution showed that endoscopic collection of pancreatic secretions 5, 10, and 15 minutes after intravenous administration of secretin is useful in screening for pancreatic insufficiency. Concomitant administration of intravenous cholecystokinin has been a subject of debate. The purpose of this study was to compare pancreatic enzyme levels after administration of secretin versus secretin plus cholecystokinin and to validate the timing of collection of duodenal fluid. METHODS: A prospective, randomized, double-blind study was conducted from September 1997 through September 1998. Patients scheduled for pancreatic enzyme sampling were randomly assigned to receive intravenous secretin (2 U/kg) plus placebo (group 1) or intravenous secretin (2 U/kg) plus cholecystokinin (0.02 microg/kg [Group 2]). Duodenal fluid was collected 5, 10, and 15 minutes later and placed in dry ice. Samples were measured for the levels of trypsin, amylase, lipase, and chymotrypsin. RESULTS: Twenty patients were assigned to each group. The age range was similar in both groups: 12 months to 16 years, 8 months in group 1 (median, 2.1 years) and 15 months to 13 years, 7 months in group 2 (median, 2.5 years). Group 2 had a greater number of patients with all four enzymes at normal levels during at least one of the time points, 75% versus 50% (P = 0.102). The difference in enzyme levels at the 5-, 10-, and 15-minute collections was statistically significant. For all four enzymes in both groups, values varied from highest to lowest with time (P = 0.0001). The enzyme levels at 10 minutes were close to the enzyme levels at 5 minutes; the lowest values occurred at 15 minutes. CONCLUSIONS: Higher pancreatic enzyme levels were obtained after administration of secretin plus cholecystokinin, although the trend did not reach statistical significance. Pancreatic enzyme levels are highest at 5 and 10 minutes, indicating that collections of duodenal fluid should be completed within 10 minutes of the administration of the secretagogues.

Adolescent↗
PubMed1984

Secretin receptors on neuroblastoma cell membranes: characterization of 125I-labeled secretin binding and association with adenylate cyclase.

Secretin, a gut-brain peptide, elicited cyclic AMP production in a clone of neuroblastoma cells derived from the C1300 mouse tumor. Adenylate cyclase (EC 4.6.1.1) in plasma membranes from these cells was stimulated by secretin greater than vasoactive intestinal peptide greater than peptide histidine isoleucine amide, but not by the related peptides glucagon, gastric inhibitory polypeptide, or human growth hormone releasing factor. Hill coefficients for stimulation approximated one and the response to submaximal peptide concentrations was additive, as expected for hormones competing for a single receptor associated with the enzyme. Binding of 125I-labeled secretin to the neuroblastoma plasma membranes was saturable, time-dependent, and reversible. The KD determined from kinetic and equilibrium binding studies approximated 1 nM. The binding site displayed marked ligand specificity that paralleled that for stimulation of adenylate cyclase. The secretin receptor was regulated by guanine nucleotides, with guanosine 5'-(beta, gamma-imino)-triphosphate being the most potent to accelerate the rate of dissociation of bound secretin. These findings demonstrate the functional association of the secretin receptor with adenylate cyclase in neuronally derived cells.

Adenylyl Cyclases↗
PubMed1988

Insulin release by glucagon and secretin: studies with secretin-glucagon hybrids.

Secretin and glucagon potentiate glucose-induced insulin release. We have compared the effects of secretin and glucagon with that of four hybrid molecules of the two hormones on insulin release and formation of cyclic AMP (cAMP) in isolated mouse pancreatic islets. All six peptides potentiated the release of insulin at 10 mM D-glucose, and their effects were indistinguishable with respect to the dynamics of release, dose-response relationship, and glucose dependency. However, measurements of cAMP accumulation in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (10(-4) M) showed that the fold increase compared with glucose alone had the following ranking order: secretin = [Tyr10, Tyr13]-secretin 1.6 less than [Tyr10, Tyr13, Trp25]secretin 1.8 less than glucagon 1.9 less than [Asp3, Glu9, Arg12]glucagon 2.3 = [Asp3, Glu9]glucagon. These results suggest that despite similar potentiating effects of secretin and glucagon on glucose-induced insulin release, their modes of action may be different.

Amino Acid Sequence↗
PubMed2001

MEK inhibits secretin release and pancreatic secretion: roles of secretin-releasing peptide and somatostatin.

We investigated the mechanism of action of methionine enkephalin (MEK) on HCl-stimulated secretin release and pancreatic exocrine secretion. Anesthetized rats with pancreatobiliary cannulas and isolated upper small intestinal loops were perfused intraduodenally with 0.01 N HCl while bile and pancreatic juice were diverted. The effect of intravenous MEK on acid-stimulated secretin release and pancreatic exocrine secretion was then studied with or without coinfusion of naloxone, an anti-somatostatin (SS) serum, or normal rabbit serum. Duodenal acid perfusate, which contains secretin-releasing peptide (SRP) activity, was collected from donor rats with or without pretreatment with MEK, MEK + naloxone, or MEK + anti-SS serum, concentrated by ultrafiltration, and neutralized. The concentrated acid perfusate (CAP), which contains SRP bioactivity, was infused intraduodenally into recipient rats. MEK increased plasma SS concentration and inhibited secretin release and pancreatic fluid and bicarbonate secretion dose-dependently. The inhibition was partially reversed by naloxone and anti-SS serum but not by normal rabbit serum. In recipient rats, CAP increased plasma secretin level and pancreatic secretion. CAP SRP bioactivity decreased when it was collected from MEK-treated donor rats; this was partially reversed by coinfusion with naloxone or anti-SS serum. These results suggest that in the rat, MEK inhibition of acid-stimulated pancreatic secretion and secretin release involves suppression of SRP activity release. Thus the MEK inhibitory effect appears to be mediated in part by endogenous SS.

Animals↗
PubMedDate not supplied

Influence of nitric oxide on the cardiovascular action of secretin in intact rats. Part A. Does nitric oxide influence the effect of secretin on arterial blood pressure?

The present study aimed to determine the influence of nitric oxide (NO) on the action of secretin in the cardiovascular system in intact rats. The studies involved the in vivo measurements of the systolic (SBP) and diastolic (DBP) blood pressure. The measurements were conducted when NO was absent, which was attained by the use of NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), and when NO was in excess which was obtained by the administration of L-arginine (L-arg), the substrate for NO synthase or exogenous donor of NO, sodium nitroprusside (SNP). Secretin given at the following three doses: 0.75, 1.5 and 3.0 micromoles/kg iv increased SBP and DBP. L-NAME inhibited the slight hypertensive effect of secretin. L-arg abolished the hypertensive effect of the peptide given at the smallest dose, did not change the effect of secretin administered at the medium dose (which did not raise the pressure) and preserved the action of the highest secretin dose. SNP abolished the hypertensive effect of all doses of the peptide. In conclusion, the study has shown that both the lack and excess of NO change the in vivo effect of secretin in intact rats.

Animals↗
PubMedDate not supplied

Evaluation of the permeability of pancreaticogastric anastomoses (PGA) with dynamic magnetic resonance pancreatography after secretin stimulation (secretin MRCP).

BACKGROUND: Because some investigators have reported the systematic occurrence of exocrine pancreatic insufficiency after pancreaticoduodenectomy with pancreaticogastric anastomosis (PGA), we assessed PGA patency after pancreaticoduodenectomy. METHODS: Nineteen patients underwent pancreaticoduodenectomy, and their PGAs were studied prospectively with secretin magnetic resonance cholangiopancreatography (MRCP). After administration of negative bowel contrast agent, single-shot fast spin-echo T2-weighted dynamic MR pancreatograms were obtained before and every minute for 12 min after secretin injection. Morphologic features of the pancreatic parenchymal and pancreatic duct were monitored (diameter and winding aspect of the pancreatic duct, pancreatic thickness, direct visualization of the anastomotic site). PGA permeability was classified into four grades, from 0 (obstruction) to 3 (good permeability). Pancreatic function was assessed by fecal-1 elastase concentration, fasting blood glucose, and fasting serum insulin level. RESULTS: MRCP grades were 0 in two patients, 1 in four, 2 in five, and 3 in eight. The anastomotic site was visualized in 10 patients. Pancreatic parenchymal atrophy was discovered in four patients. There were statistically significant relations between secretin MRCP permeability grade and fecal-1 elastase concentration (p < 0.03) and between secretin MRCP permeability grade and pancreatic atrophy (p < 0.005). In contrast, fecal-1 elastase concentration was lower than the normal value in all but one case. There was no statistically significant relation between fecal-1 elastase concentration and other morphologic data. CONCLUSION: Secretin MRCP may indicate PGA stenosis or dysfunction, but it is not the only factor suggesting exocrine pancreatic insufficiency. Thus the major role of PGA may be the preservation of long-term endocrine function.

Anastomosis, Surgical↗
PubMed2003

Spatial approximation between two residues in the mid-region of secretin and the amino terminus of its receptor. Incorporation of seven sets of such constraints into a three-dimensional model of the agonist-bound secretin receptor.

Photoaffinity labeling of receptors by bound agonists can provide important spatial constraints for molecular modeling of activated receptor complexes. Secretin is a 27-residue peptide hormone with a diffuse pharmacophoric domain that binds to the secretin receptor, a prototypic member of the Class B family of G protein-coupled receptors. In this work, we have developed, characterized, and applied two new photolabile probes for this receptor, with sites for covalent attachment in peptide positions 12 and 14, surrounding the previously most informative site of affinity labeling of this receptor. The [Tyr10,(BzBz)Lys12]rat secretin-27 probe covalently labeled receptor residue Val6, whereas the [Tyr10,(BzBz)Lys14]rat secretin-27 probe labeled receptor residue Pro38. When combined with previous photoaffinity labeling data, there are now seven independent sets of constraints distributed throughout the peptide and receptor amino-terminal domain that can be used together to generate a new molecular model of the ligand-occupied secretin receptor. The amino-terminal domain of this receptor presented a stable platform for peptide ligand interaction, with the amino terminus of the peptide hormone extended toward the transmembrane helix domain of the receptor. This provides clear insights into the molecular basis of natural ligand binding and supplies testable hypotheses regarding the molecular basis of activation of this receptor.

Amino Acid Sequence↗
PubMed1990

Effect of propranolol on secretin-induced gastrin release and secretin-induced tachycardia in patients with the Zollinger-Ellison syndrome.

The mechanism for secretin-induced gastrin release in the Zollinger-Ellison syndrome is uncertain. We evaluated whether the stimulatory effect of intravenous secretin on gastrin release was partly mediated through a beta-adrenergic stimulatory mechanism. Serum gastrin concentrations and heart rate were monitored in six patients with the Zollinger-Ellison syndrome. Secretin (2 clinical units/kg) increased mean serum gastrin concentrations from 1558 pg/ml basally to a peak of 3683 pg/ml (136% above baseline). This increase was not altered by pretreatment with 2 mg of propranolol intravenously, a dose which in previous studies blocked terbutaline-induced gastrin release. Secretin increased heart rate by 14 beats/min (20% above base-line) and this also was not altered by propranolol pretreatment. Thus, the stimulatory effects of secretin on gastrinoma cells and the heart do not appear to be mediated by beta-adrenergic receptors.

Adult↗
PubMed1991

Differential effects of secretin-fragments imply a dual mechanism of action for secretin.

The effects of synthetic peptides, representing different parts of the secretin molecule in isolated mouse pancreatic islets have been investigated in perifusion studies. In the presence of 10 mM D-glucose the C-terminal nonapeptide Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH2 (S19-27) showed a 2-fold higher activity than that earlier shown for S22-27 and had the same effect on the dynamic pattern of insulin release as secretin, while the elongating sequence Leu-Gln-Arg (S19-21) had no effect on the insulin release. The nonapeptide Leu-Ser-Arg-Leu-Arg-Asp-Ser-Ala-Arg (S10-18) had no influence on the insulin release. Glucagon release seen after intact secretin could not be shown for any of the smaller fragments. Accumulation of cAMP in the islets as seen with secretin, could at 10 mmol/L D-glucose only be demonstrated with S22-27 or S19-27 but not with S10-18 or S1-6. Our results indicate that full size secretin has to be present to stimulate glucagon release while insulin-releasing activity can be confined to the C-terminal part of the hormone.

Amino Acid Sequence↗
PubMed1977

Plasma secretin and pancreatic bicarbonate response to exogenous secretin in man.

The dose response of duodenal bicarbonate production during synthetic porcine secretin infusions was studied in six healthy volunteers and related to plasma secretin immunoreactivity. Secretin was infused in each individual at four different doses from 0-1 to 2-7 CU/kg/h, each infusion lasting for 60 minutes. Mean maximal bicarbonate secretion was 33 +/- 4 mEq/h. The secretin plasma level for half maximal bicarbonate response was estimated to be 22 pmol/l. As this level is reported to be achieved by intraduodenal acidification in man, it is concluded that secretin may well play a part in the control of duodenal pH.

Adult↗
PubMed2002

Interaction among four residues distributed through the secretin pharmacophore and a focused region of the secretin receptor amino terminus.

The amino terminus of the secretin receptor (SecR) is known to be critical for natural agonist action, although the role it plays is still unclear. We have demonstrated that photolabile residues within both the amino-terminal (position 6) and carboxyl-terminal (positions 22 and 26) halves of secretin each covalently label receptor amino-terminal tail residues [Dong et al., J Biol Chem, 274:19161-19167 (1999), 274:903-909 (1999), and 275:26032-26039 (2000)]. Here, we extend this series of studies with an additional probe having its site of covalent attachment in a distinct region of the peptide, between amino- and carboxyl-terminal helical domains. This probe incorporated a photolabile (epsilon-p-benzoylbenzoyl)lysine in position 18 and a site for oxidative radioiodination [(tyrosine(10),(benzoyl-benzoyl)lysine(18))rat secretin-27]. This analog represented a full agonist, stimulating cAMP accumulation in Chinese hamster ovary-SecR cells in a concentration-dependent manner. It bound to the SecR specifically and saturably, and was able to efficiently label that molecule within its amino terminus. Sequential specific cleavage, purification, and sequencing demonstrated that this probe labeled receptor residue arginine(14), in the same subdomain as that labeled by previous probes. Consistent with the importance of this residue, alanine replacement mutagenesis (R14A) resulted in substantial reductions in the potency (127-fold) and binding affinity (400-fold) of secretin relative to its action at the wild-type receptor. We have been able to accommodate all four extant pairs of residue-residue approximations between divergent regions of the secretin pharmacophore and the first forty residues of the SecR into a credible molecular model of this interaction. Additional experimentally derived constraints will be necessary to determine the spatial positioning of this complex with the remainder of the SecR.

Amino Acid Sequence↗
PubMed1976

Plasma levels of secretin in man and dogs: validation of a secretin radioimmunoassay.

We have developed and validated a secretin radioimmunoassay that is sufficiently sensitvie to measure circulating levels of secretin in the plasma of man and dogs. At a final dilution of 1:50,000, the antibody bound 30 percent to 40 percent of radioiodinated (125 I) 6-tyrosyl synthetic secretin. Pure natural porcine secretin was used as a reference standard and a linear dose-response curve was generated with 10 to 1,000 pg. of the polypeptide. Little or no cross-reactivity was found when graded doses of other gastrointestinal polypeptides were assayed in the radioimmunoassay and immunoreactive secretin (IRS) in volumes of serum up to 300 mul could be measured accurately.

Animals↗