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PubMed1981

Characterization of the VIP- and secretin-stimulated adenylate cyclase system from human lung.

The response of a crude particulate adenylate cyclase preparation from surgically removed human lung to guanine nucleotides, sodium fluoride, beta-adrenergic agonists, prostaglandins, vasoactive intestinal peptide (VIP), secretin, and [Val5]secretin was investigated. The enzyme activity increased 5, 10, and 9-fold, respectively, with GTP, Gpp(NH)p, and sodium fluoride. This activity was stimulated (in the presence as well as in the absence of added GTP) by D,L-isoproterenol, L-epinephrine and L-norepinephrine, the relative potency of these agonists being compatible with the existence of beta-adrenoceptors of the beta2 subtype. Prostaglandins E1 and E2, but not PGF1alpha and PGF2alpha, stimulated the enzyme, PGE1 being at least 10 times more potent than PGE2. The biphasic pattern of stimulation of the same adenylate cyclase activity by VIP suggested the presence of high- and low-affinity VIP receptors coupled to the enzyme. This stimulation by VIP was not inhibited by secretin-(7-27). The stimulation of adenylate cyclase by secretin and [Val5]secretin was also biphasic, suggesting the coexistence of high- and low-affinity secretin receptors. Secretin-(7-27) was able to inhibit completely the secretin stimulation acting through high-affinity secretin receptors but exerted no effect on the stimulation operating through low-affinity secretin receptors, which might indicate that the latter receptors were in fact "VIP-preferring receptors". [Val5]secretin was also used to differentiate these peptide receptors, since its properties were more VIP-like than those of secretin.

Adenylyl Cyclases↗
PubMed1981

Plasma secretin concentrations and gastric pH in healthy subjects and patients with digestive diseases.

Plasma secretin concentrations were determined in healthy subjects and patients with duodenal ulcer, achlorhydria, and celiac sprue. Mean fasting plasma secretin concentrations in 26 healthy subjects and 26 duodenal ulcer patients were 6.7 +/- 0.5 and 10.2 +/- 1.2 pg/ml, respectively, and were significantly different (P less than 0.02). After ingestion of a standard meat meal, pyloric pH decreased to less than 4.5 within 15 min and plasma secretin concentrations significantly increased in all 52 subjects. In 14 subjects (seven healthy subjects and seven patients with duodenal ulcer), no significant rise in plasma secretin concentration occurred when pyloric pH was maintained at greater than 5.0 by intravenous cimetidine (600 mg) and intragastric antacid. In 10 achlorhydric patients, intragastric pH remained greater than 5.0 after the meal and plasma secretin concentrations did not change. However, plasma secretin concentrations increased significantly when 0.1 N HCl was infused in the stomach (25 mEq/hr) during the postprandial period. In all eight adult patients with celiac disease (seven untreated, one partially treated), pyloric pH remained less than 4.0 after a meal. Postprandial secretin concentrations did not increase significantly in six and showed a transient rise in two. These studies show that (1) plasma secretin concentration increases significantly after meals in healthy subjects and patients with duodenal ulcer; (2) neutralization of gastric acid and the achlorhydric state show no significant postprandial rise in plasma secretin concentration; (3) achlorhydric patients do not have a defect in secretin release in response to acid; and (4) failure of postprandial rise in plasma secretin in patients with celiac disease is attributed to impaired release of secretin and in achlorhydric patients it is attributed to lack of acid secretion.

Achlorhydria↗
PubMed2003

Secretin, 100 years later.

One hundred years have elapsed since the discovery of secretin by Bayliss and Starling in 1902. In the past century, the research of secretin has gone by many milestones including isolation, purification and structural determination, chemical synthesis, establishment of its hormonal status by radioimmunoassay and immunoneutralization, identification of the specific receptor, cloning of secretin and its receptor, and identification of a secretin-releasing peptide. It has become clear that secretin is a hormone-regulating pancreatic exocrine secretion of fluid and bicarbonate, gastric acid secretion, and gastric motility. The release and actions of secretin is regulated by hormone-hormonal and neurohormonal interactions. The vagus nerve, particularly its afferent pathway, plays an essential role in the physiological actions of secretin. Substantial information about the property of the secretin receptor has been accumulated, but a potent secretin receptor-specific antagonist remains to be formulated. The neural regulatory mechanisms of the release and action of secretin await further elucidation. The physiological role of secretin in intestinal secretions and motility and extragastrointestinal organs remains to be defined. The presence of secretin and its receptor in the central nervous system is well documented, but its function as a neuropeptide has been recognized gradually and requires extensive study in the future.

Animals↗
PubMed1999

Role of charged amino acids conserved in the vasoactive intestinal polypeptide/secretin family of receptors on the secretin receptor functionality.

The secretin receptor is a member of a large family of G-protein-coupled receptors that recognize polypeptide hormone and/or neuropeptides. Charged, conserved residues might play a key role in their function, either by interacting with the ligand or by stabilizing the receptor structure. Of the four charged amino acids that are conserved in the whole secretin receptor family, D49 and R83 (in the N-terminal domain) were probably important for the secretin receptor structure: replacement of D49 by H or R and of R83 by D severely reduced both the maximal response to secretin and its potency. No functional secretin receptor could be detected after replacement of R83 by L. Mutation of D49 to E, A, or N had no effect or reduced 5-fold the potency of secretin. The highly conserved positive charges found at the extracellular ends of TM III (K194) and IV (R255) were important for the secretin receptor function, as K194 mutation to A or Q and R255 mutation to Q or D decreased the secretin's affinity 15- to 1000-fold, respectively. Six extracellular charged residues are conserved in closely related receptors but not in the whole family. K121 (TM I) and R277 (TM V) were not important for functional secretin receptor expression. D174 (TM II) was necessary to stabilize the active receptor structure: the D174N mutant receptors were unable to stimulate normally the adenylate cyclase in response to secretin, and functional D174A receptors could not be found. Mutation of R255, E259 (second extracellular loop), and E351 (third extracellular loop) to uncharged residues reduced only 10- to 100-fold the secretin potency without changing its efficacy: these residues either stabilized the active receptor conformation or formed hydrogen rather than ionic bonds with secretin. Mutation of K121 (TM I) to Q or L and of R277 (TM V) to E or Q did not affect the receptor functional properties.

Adenylyl Cyclases↗
PubMed1977

Synthesis of phenolic group containing analogues of porcine secretin and their immunological properties.

Syntheses by the conventional method are described of Nalpha-tyrosylsecretin, [Tyr1]secretin, and Nalpha-beta-(4-hydroxyphenyl)propionylsecretin. Secretin and [Tyr6]secretin were also prepared by the synthetic route identical with those employed for construction of the above analogues. Purification of secretin and the analogues was conducted by ion-exchange column chromatography on CM-Sephadex and gel filtration. Immunological reactivities of these analogues were examined in the radioimmunoassay system for secretin using two different antisera raised against synthetic secretin in rabbits. The tracers used in this study were [125I]-[Tyr1]secretin and [125I]-[Tyr6]secretin. The dose-response curves of Nalpha-tyrosylsecretin, [Tyr1]secretin, and Nalpha-beta-(4-hydroxphenyl)propionylsecretion were essentially superimposable upon those of natural and synthetic preparations of porcine secretin in the systems used, while [Tyr6]secretin showed discrepancy in the curve. In addition, biological activities of the synthetic polypeptides were compared with that of natural porcine secretin in term of exocrine pancreatic secretory response in anesthetized dogs.

Amino Acid Sequence↗
PubMed1999

Comparison of ultrasound-secretin test and sphincter of Oddi manometry in patients with recurrent acute pancreatitis.

Manometry is considered the gold standard for evaluating sphincter of Oddi dysfunction. It has recently been demonstrated that the ultrasound (US) secretin test proposed a few years ago as a noninvasive test for the study of sphincter of Oddi dysfunction yields a substantial percentage of pathological findings in patients with acute recurrent pancreatitis. The aim of this study was to compare the results of the US secretin test with sphincter of Oddi manometry findings in a consecutive series of patients with recurrent acute pancreatitis. Forty-seven patients admitted to our gastrointestinal unit suffering from recurrent acute pancreatitis underwent ultrasonographic measurement of the main pancreatic duct at baseline and for 60 min after maximal stimulation with secretin at 1 IU/kg. According to the US secretin test findings in 35 healthy control subjects, the test results were considered to indicate pathology when the duct was still dilated after 20 min. Within three to seven days the same patients underwent perendoscopic manometry. Thirty-six patients (17 men, 19 women; mean age 41 +/- 15 years) had a successful US secretin test and sphincter of Oddi manometry. Eleven patients (30.6%) presented normal manometric findings. Two of these had an abnormal US secretin test. Twenty-five patients had abnormal manometry findings, revealing stenosis in 19 (52.7%) (17 with abnormal US secretin test) and dyskinesia in six (five with an abnormal US secretin test). Compared to manometry findings, the US secretin test sensitivity and specificity for sphincter of Oddi dysfunction were 88% and 82%, respectively. In conclusion, most patients with recurrent acute pancreatitis have sphincter of Oddi dysfunction documented by both at the US secretin test and sphincter of Oddi manometry; results of the US secretin test are reliable compared to sphincter of Oddi manometry, and therefore the US secretin test may offer a valid alternative to the more expensive and invasive manometric procedure for assessing sphincter of Oddi dysfunction in patients with recurrent acute pancreatitis.

Acute Disease↗
PubMed1998

A role for receptor kinases in the regulation of class II G protein-coupled receptors. Phosphorylation and desensitization of the secretin receptor.

The secretin receptor is a member of a structurally distinct class of G protein-coupled receptors designated as Class II. The molecular mechanisms of secretin receptor signal termination are unknown. Using transiently transfected HEK 293 cells expressing the secretin receptor, we investigated its mechanisms of desensitization. Binding of [125I]-secretin to plasma membranes of receptor-expressing cells was specific, with a Kd of 2 nM. Secretin evoked an increase in cellular cAMP with an EC50 of 0.4 nM. The response was maximal by 20 min and desensitized rapidly and completely. Immunoprecipitation of a functional, N-terminal epitope-tagged secretin receptor was used to demonstrate agonist-dependent receptor phosphorylation, with an EC50 of 14 nM. Pretreatment with protein kinase A or C inhibitors failed to alter secretin-stimulated cAMP accumulation. G protein-coupled receptor kinases (GRKs) are known to be involved in the desensitization of Class I G protein-coupled receptors; therefore, the effect of cotransfection of GRKs on secretin-stimulated cAMP signaling and phosphorylation was evaluated. GRKs 2 and 5 were the most potent at augmenting desensitization, causing a 40% reduction in the maximal cAMP response to secretin. GRK 5 also caused a shift in the EC50 to the right (p < 0.05). GRK 4 and GRK 6 did not alter dose-dependent signaling, and GRK 3 was intermediate in effect. Receptor phosphorylation correlated with desensitization for each GRK studied, whereas second messenger-dependent kinase phosphorylation appeared to be less important in secretin receptor signal termination. We demonstrate agonist-dependent secretin receptor phosphorylation coincident with profound receptor desensitization of the signaling function in HEK 293 cells, suggesting a role for receptor phosphorylation in this paradigm. Although GRK activity appears important in secretin receptor desensitization in HEK 293 cells, protein kinases A and C appear to play only a minor role. These results demonstrate that the GRK-arrestin system regulates Class II G protein-coupled receptors.

Cell Line↗
PubMed1986

Secretin stimulates cyclic AMP formation in the rat brain.

The effects of secretin on cyclic AMP levels in the rat brain were determined. Incubation of rat brain frontal cortex slices with secretin or the structurally related peptides peptide histidine leucine (PHI) or vasoactive intestinal polypeptide (VIP) in the presence of 10 mM theophylline resulted in a dose-dependent increase in the cyclic AMP levels. The half-maximal increase in cyclic AMP occurred using a 1 microM dose of secretin or a 2 microM dose of PHI or VIP. Preincubation of slices with secretin-(5-27) produced a dose-dependent inhibition of the secretin but not VIP- or PHI-stimulated increase in the cyclic AMP content. Also, in receptor binding studies, secretin-(5-27) produced a dose-dependent inhibition (Ki = 400 nM) of 125I-secretin but not of 125I-VIP binding to rat brain membranes. Guanyl-5'-yl imidodiphosphate decreased the affinity of radiolabelled secretin binding as a result of an increased rate of dissociation of bound 125I-secretin. These data suggest that secretin receptors in the rat brain may be coupled to adenylate cyclase in a stimulatory manner and that secretin-(5-27) may function as a central secretin receptor antagonist.

Amino Acid Sequence↗
PubMed1975

Effects of secretin on insulin secretion and glucose tolerance.

Effects of intravenous (IV) infusion of secretin during IV infusion of glucose were examined in normal men. Secretin was administered according to three schedules: with each schedule a comparable priming dose was delivered in the first minute, but this was followed by a maintained (120 min) infusion of secretin at a relatively high rate, or by maintained infusion at one-third that rate, or by brief (15 min) infusion at the lower rate. The lower infusion rate produced increments in secretin in the blood within the range attainable during endogenous secretion. By comparison with effects of glucose alone each secretin infusion enhanced the increments of immunoreactive insulin in the blood. Enhancement of the early release (0-5 min) of insulin was similar with each type of secretin infusion, but the integrated changes in insulin levels through the total infusion period were related to the total doses of secretin. With each dose of secretin glucose tolerance was improved but the three mean glucose curves observed during infusions of secretin were not distinguishable from one another in spite of widely different integrated insulin responses. Secretin did not modify suppression of immunoreactive glucagon or free fatty acids in the blood during hyperglycemia. The results suggest that the effect of continuous administration of secretin on glucose tolerance is not simply related to its integrated insulinotropic action. It is suggested that the effect may be highly dependent on enhancement of insulin secretion early in the response to glycemia, or that it may be due to effects of secretin on glucose production or disposal which are not mediated by insulin.

Blood Glucose↗
PubMed1993

Effect of [(CH2NH)4,5]secretin on pancreatic exocrine secretion in guinea pigs and rats.

[psi 4,5]Secretin was shown to be a secretin receptor antagonist that inhibits secretin-stimulated increase in adenosine 3',5'-cyclic monophosphate in isolated pancreatic acini of the guinea pig. To determine whether it inhibits pancreatic exocrine secretion in vivo, we have studied the effect of [psi 4,5]secretin on the pancreatic secretion stimulated by secretin in anesthetized guinea pigs and rats. In basal state, [psi 4,5]secretin given intravenously for 2 or 3 h in varying doses of 1.6-32.7 nmol.kg-1.h-1 dose dependently increased pancreatic secretion of both fluid and bicarbonate during the 1st h, but it returned gradually to basal level within 2 or 3 h. On the other hand, [psi 4,5]secretin significantly inhibited the pancreatic secretion stimulated by either exogenous or endogenous secretin in a dose-related manner. The inhibitory effect of [psi 4,5]secretin in guinea pigs was greater than that in rats. However, it did not completely block the secretin-stimulated pancreatic secretion, whereas a rabbit antisecretin serum suppressed it completely. We conclude that 1) in the unstimulated state, [psi 4,5]secretin is a partial agonist of pancreatic exocrine secretion of both fluid and bicarbonate; and 2) when pancreatic secretion is stimulated by secretin, unlike an antisecretin serum, it is a partial inhibitor in intact guinea pigs and rats.

Animals↗
PubMed1995

Secretin at physiological doses inhibits gastric motility via a vagal afferent pathway.

Secretin is an important modulator of gastric motility. In this study, we investigated the site(s) and mechanism(s) of action of secretin to inhibit gastric motility, using an in vivo rat model. Intragastric pressure response to graded doses of secretin was recorded in anesthetized rats by a balloon attached to a catheter passed through an incision in the duodenum into the body of the stomach. The intragastric pressure was set at 10 cmH2O with balloon distension. Intravenous infusion of secretin (1.4, 2.8, 5.6, 11.2, and 22.4 pmol.kg-1.h-1) decreased intragastric pressure in a dose-dependent manner. The threshold dose was 2.8 pmol.kg-1.h-1, and the effective dose at 50% (ED50) was 5.6 pmol.kg-1.h-1, which produced physiological levels of plasma secretin. Pretreatment with hexamethonium (10 mg/kg) markedly reduced gastric motor response to secretin (5.6 pmol.kg-1.h-1). Bilateral truncal vagotomy also significantly diminished gastric motor responses to secretin. In contrast, secretin (5.6 pmol.kg-1.h-1) had no effect on gastric contraction evoked by electrical vagal stimulation (1.25-5 Hz) or carbachol (10(-6) to 3 x 10(-5) M). These observations indicate that physiological concentrations of secretin act via stimulation of presynaptic cholinergic neurons in a vagally mediated pathway. In subsequent studies, we demonstrated that perivagal treatment 4 days before with the sensory neurotoxin, capsaicin, abolished gastric motor response to secretin but did not affect contraction evoked by electrical vagal stimulation. Similarly, we also showed that gastroduodenal application of capsaicin for 30 min also markedly reduced gastric response to secretin. These observations indicate that physiological doses of secretin act on vagal afferent pathways originating from the gastroduodenal mucosa to induce gastric relaxation.

Afferent Pathways↗
PubMed1970

The gastrointestinal stimulus to insulin release. II. A dual action of secretin.

The insulin release after an oral glucose load is both earlier and greater than would be expected from the glycemic stimulus. This augmentation of insulin release has been attributed to humoral factors from the gut. It has been previously demonstrated that secretin is released very rapidly after oral glucose and postulated that it acts as an early trigger to insulin release. This effect would not explain the magnitude of the peak insulin response which occurs about 30 min after peak secretin levels. The present studies, however, demonstrate an additional action of secretin which may explain this. To further study the role of secretin in insulin release in normal subjects, two consecutive 20 min intravenous glucose infusions were administered 150 min apart with and without an intervening secretin infusion (10 U) given to approximate serum secretin levels seen after oral glucose ingestion. A highly significant (P<0.01) potentiation of the insulin response to the post-secretin glucose infusion was observed. This occurred both when secretin was given 7 min or 25 min before glucose. In the latter case, serum secretin was undetectable during the glucose infusion. These studies demonstrate that secretin potentiates the glycemic release of insulin. Despite the augmented insulin response, no consistent change in blood glucose variation was observed. This is consistent with the suggestion that the facilitated disposal of an alimentary glucose load is not dependent solely on enhanced insulin secretion. Secretin appears to have a dual role in insulin release, an early direct stimulation followed by a prolonged potentiation of the glycemic stimulus. The potentiating effect is of such magnitude to suggest that secretin is the dominant factor in the enteric component of insulin release after an oral glucose load.

Adolescent↗
PubMed1984

Role of endogenous secretin in acid-induced inhibition of human gastric function.

The role of secretin in the inhibition of gastric acid secretion that occurs during acidification of the gastric lumen was studied in nine healthy men. Gastric acid secretion was stimulated by 500-ml meals of 8% peptone solution, and the pH of the stomach was maintained at 5.5, 2.5, or 2.0 by intragastric titration. The increase in plasma secretin was measured, after extraction, by a new secretin radioimmunoassay. After determining the intravenous dose of secretin required to reproduce plasma secretin concentrations achieved during pH 2.5 and 2.0 meals, similar doses were given during administration of a pH 5.5 peptone meal. The doses of secretin led to plasma secretin concentrations that averaged 3.4 pM, not different from the 3.2 and 3.9 pM concentrations achieved during acidified meals. However, exogenous secretin infusion failed to inhibit acid secretion or gastrin response to peptone, although significant inhibitions occurred in both during peptone meals given at pH 2.5 or 2.0. When secretin infusions were given at fivefold higher rates, plasma gastrin responses again failed to demonstrate significant inhibition. Gastric emptying was inhibited significantly by both acidified peptone meals but only slightly (P = 0.053) during exogenous infusion of physiologic secretin doses. The decrease in acid secretion could be explained by decreased gastrin release, but neither of these findings could be explained by circulating secretin concentrations. These results cast strong doubt on a physiological role of secretin in inhibition of acid secretion in man.

Adult↗
PubMed1977

The augmentation effects of secretin on the insulin responses to known stimuli: specificity for glucose.

Secretin stimulates insulin release directly and augments insulin responses when administered prior to an insulinogenic stimulus. The magnitude and specificity of this augmentation effect of secretin pretreatment was evaluated in normal subjects to pulses of the following stimuli: 5 g glucose (n = 6), 1 g arginine (n = 8), 2 microgram isoproterenol (n = 6), 0.5 g tolbutamide (n = 5) and 0.5 mg glucagon (n = 6). Secretin was administered either as a 15 U pulse with a 3 U/min infusion for 25 min or as 4-150 U pulses. A period of 30 min elapsed after either the cessation of the infusion or the final 150 U pulse. In all studies, the acute insulin responses immediately following secretin were observed and had returned to baseline levels prior to the administration of any insulinogenic stimulus. Secretin only augmented the acute insulin responses to 5 g glucose pulses (pre-secretin glucose; 28 +/- 20 muU/ml, mean +/- SD; post-secretin glucose pulse: 45 +/- 37 muU/ml, P less than 0.5), an increase of 56 +/- 21% (P less than .005). A highly linear relationship was noted (r = .98, P less than .01) between the acute insulin response to glucose before and after secretin suggesting that the insulin response to the control glucose pulse is a major determinant of the glucose stimulated response after secretin. Secretin pretreatment did not augment the insulin responses to arginine, isoproterenol, tolbutamide and glucagon. The specificity of secretin for augmenting glucose stimulated insulin release suggets a possible role for secretin in carbohydrate metabolism.

Adult↗
PubMed1995

[Preparation of specific antiserum of secretin and its use in time-resolved fluoroimmunoassay].

We have prepared a specific anti-secretin antiserum and developed a sensitive time-relevant fluoroimmunoassay (TR-FIA) for secretin. An anti-secretin antiserum was produced in rabbit by immunization with synthetic secretin C-terminal 8 residue conjugate to chicken serum albumin as antigen. The TR-FIA was based on the competition between free secretin and biotinylated secretin as a tracer for rabbit anti-secretin antibodies on a goat anti-rabbit IgG antibody coated microtiter plate. After separation of bound and free fractions, a solution of europium (III) ion chelate labeled streptavidin (Eu-SA) was added to the biotinylated secretin bound on the microtiter plate. The microtiter plate was washed and then Eu-SA activity was measured by time-resolved fluorometry. In this TR-FIA, the measurable range of secretin was from 2.5 to 100 pg/assay and the specificity was less than 0.01% against other peptide hormones. For the measurement of secretin in the human plasma, a sample was required for the pretreatment in order to separate from interfering substances. The mean recovery of secretin using commercially reverse phase column was 80.2% (n = 11). The plasma secretin concentrations of normal subjects and those with various diseases could be measured by this proposed TR-FIA.

Animals↗
PubMed2003

Neural control of the release and action of secretin.

The release and physiological actions of secretin on pancreatic exocrine secretion and gastric secretion of acid and motility are regulated by neuro-hormonal control. The release of secretin by duodenal acidification is mediated by a secretin releasing peptide (SRP). The release and action of SRP are neurally mediated depending on vagal afferent pathway. SRP activity in acid perfusate of the duodenum was substantially decreased when rats were treated with tetradotoxin (TTX), perivagal application of capsaicin, a beta-adrenergic blocker, Met-enkephalin (MEK) or vagotomy. The release of secretin by SRP was abolished in rats treated with TTX, mucosal or perivagal application of capsaicin, MEK or vagotomy. Both release of secretin and pancreatic exocrine secretion (PES) elicited by duodenal acidification were also inhibited dose-dependently by Met-enkepahlin, 5-HT(2) antagonist, ketanserin and 5-HT(3) antagonist, ondansetron. Stimulation of PES and inhibition of gastric acid secretion and motility by secretin in a physiological dose are also dependent on the vagal afferent pathway as these effects of secretin are abolished by perivagal capsaicin treatment or vagotomy. In conscious rats, vagotomy, vagal ligation, or perivagal colchicine but not capsaicin treatment reduced the number of secretin binding sites in the forestomach suggesting another mode of neural regulation that affects gastric motility. Except in the rat, stimulation of PES by secretin in a physiological dose is profoundly inhibited by atropine indicating the importance of a cholinergic input. In isolated and perfused rat pancreas, electrical field stimulation potentiated secretin-stimulated PES that was suppressed by atropine and anti-GRP serum, suggesting the roles of intrapancreatic cholinergic and GRP-containing neurons. In rats, secretin-stimulated PES was inhibited by a NO synthase inhibitor suggesting mediation by NO. However, the neuropeptides and neurotransmitters involved in regulation of the release and action of secretin and their sites of action remain to be elucidated.

Animals↗
PubMed1991

The secretin precursor gene. Structure of the coding region and expression in the brain.

Secretin is a 27-amino acid gastrointestinal hormone that stimulates the secretion of bicarbonate-rich pancreatic fluid. We isolated and analyzed the coding region of the gene for the rat secretin precursor. The entire coding region spans 692 base pairs and is divided into four regions corresponding to the signal peptide and NH2-terminal peptide, the secretin peptide and processing signal sequences, a part of the COOH-terminal peptide, and the remainder of the COOH-terminal peptide, which are interrupted by three short introns (81, 105, and 104 base pairs). The organization is similar to those of the genes for other members of the secretin family, glucagon and VIP/PHI-27 precursors, supporting the assumption that the genes for the secretin family peptide precursors originated from a common ancestral gene. We also demonstrated that the secretin precursor gene is widely expressed in the brain and in the hypophysis. The regional expression pattern of the secretin precursor gene in the brain is quite different from those of the glucagon and VIP/PHI-27 precursor genes. The secretin precursor gene is highly expressed in the medulla oblongata and pons of the brain and the hypophysis, the expression levels of which are comparable to those in the duodenum. The secretin precursor mRNA in the brain and the hypophysis has the same coding sequence as that in the duodenum, indicating that secretin in the brain and the hypophysis is produced from the same secretin precursor protein as that in the duodenum. This is the first evidence to be reported that the secretin precursor gene is definitely expressed in the brain.

Amino Acid Sequence↗
PubMed1977

Radioimmunoassay measurement of secretin half-life in man.

High titer antibodies to secretin were produced in rabbits by immunization with purified porcine secretin (from GIH) conjugated to bovine serum albumin in complete Freund's adjuvant. Synthetic porcine secretin (from Squibb) was radiolabeled with 125I using chloramine-T and radiosecretin was purified using talc-silica and fibrocellulose powder. Specificity of antibodies to secretin was extensively evaluated in studies examining (1) cross-reactivity with other naturally occurring hormones, (2) parellelism of serum dilutions and secretin standards, (3) quantitative recovery of secretin added to serum samples, and (4) changes in circulating immunoreactive secretin in response to intraduodenal acidification. The mean fasting serum secretin concentration in 10 dogs was 65 +/- 5 (SEM) pg per ml and in 21 healthy human volunteers it was 69 +/- 5 pg per ml. In response to intraduodenal instillation of 10 mEq of HCl, portal venous secretin concentrations increased from a mean fasting value of 52 to 450 pg per ml within 2 min; peripheral venous secretin increased from 66 to 229 pg per ml within 5 min. No significant changes in peripheral serum immunoreactive secretin concentrations were identified in dogs after a protein meal. Intravenously administered secretin in man disappeared from the circulation with mean half-life 4.06 +/- 0.82 (SEM) min.

Animals↗