DOCSLIB.ORG

Vagal, Cholinergic Regulation of Pancreatic Polypeptide Secretion

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Vagal, Cholinergic Regulation of Pancreatic Polypeptide Secretion Vagal, Cholinergic Regulation of Pancreatic Polypeptide Secretion T. W. Schwartz, … , O. B. Schaffalitzky de Muckadell, F. Stadil J Clin Invest. 1978;61(3):781-789. https://doi.org/10.1172/JCI108992. Research Article The effect of efferent, parasympathetic stimulation upon pancreatic polypeptide (PP) secretion was studied in three ways: (a) Plasma PP concentrations increased in response to insulin-induced hypoglycemia in both normal subjects, from 11 pM (9.5-12.5) to 136 pM (118-147), n = 8 (median and interquartile range) and in duodenal ulcer patients, from 33 pM (21- 52) to 213 pM (157-233), n = 7. The PP response to hypoglycemia was diminished by atropine in normal subjects P( < 0.005) and completely abolished by vagotomy in the duodenal ulcer patients. (b) Electrical stimulation, 8 Hz, of the vagal nerves in anesthetized pigs induced an increase in portal PP concentrations within 30 s from 32 pM (28-39) to 285 pM (248-294), n = 12. Minimal stimulatory frequency was 0.5 Hz and maximal stimulatory frequency 8-12 Hz. Atropine inhibited the PP response to electrical stimulation. Median inhibition with 0.5 mg of atropine/kg body wt was 74%, range 31-90%, n = 6. The response was eliminated by hexamethonium. Adrenergic alpha and beta blockade did not influence the release of PP in response to vagal stimulation. (c) Acetylcholine stimulated, in a dose-dependent manner, the secretion of PP from the isolated perfused porcine pancreas, half-maximal effective dose being 0.19 μM; maximal PP output in response to 5 min stimulation was 228 pmol, range 140-342 pmol, n = 5. Atropine […] Find the latest version: https://jci.me/108992/pdf Vagal, Cholinergic Regulation of Pancreatic Polypeptide Secretion T. W. SCHWARTZ, J. J. HOLST, J. FAHRENKRUG, S. LINDKLER JENSEN, 0. V. NIELSEN, J. F. REHFELD, 0. B. SCHAFFALITZKY DE MUCKADELL, and F. STADIL, Institute of Medical Biochemistry, University of Aarhus, Arhus; Department of Clinical Chemistry, Bispebjerg Hospital, Copenhagen; Department of Surgical Gastroenterology C, Rigshospitalet, Copenhagen, Denmark A B S R A C T The effect of efferent, parasympathetic INTRODUCTION stimulation upon pancreatic polypeptide (PP) secre- Human pancreatic polypeptide was isolated by Chance tion was studied in three ways: (a) Plasma PP concen- et al. as a side fraction during insulin purification (1). trations increased in response to insulin-induced hypo- It is a 36 amino acid straight chain polypeptide with no glycemia in both normal subjects, from 11 pM (9.5- similarity in sequence to any other known hormone. 12.5) to 136 pM (118-147), n = 8 (median and inter- One or two aminoacids distinguish the known mam- quartile range) and in duodenal ulcer patients, from 33 malian pancreatic polypeptides (PP)l (1), whereas they pM (21-52) to 213 pM (157-233), n = 7. The PP re- have only 16 amino acids in common with the avian sponse to hypoglycemia was diminished by atropine in counterpart (2). normal subjects (P < 0.005) and completely abolished PP has been localized to secretory granules in a spe- by vagotomy in the duodenal ulcer patients. (b) Electri- cific endocrine cell type in the pancreas distinct from cal stimulation, 8 Hz, of the vagal nerves in anesthe- the A, B, D, and D, cells (3, 4). PP cells are found tized pigs induced an increase in portal PP concentra- both in the islets and in the acinar tissue and duct tions within 30 s from 32 pM (28-39) to 285 pM (248- epithelium. In some species PP cells are numerous 294), n = 12. Minimal stimulatory frequency was 0.5 in the extra-insular tissue and concentrated towards the Hz and maximal stimulatory frequency 8-12 Hz. Atro- duodenal part ofthe pancreas, whereas e.g., in the islets pine inhibited the PP response to electrical stimula- of the sheep the PP cells nearly outnumbers the insulin tion. Median inhibition with 0.5 mg of atropine/kg body cells (4). wt was 74%, range 31-90%, n = 6. The response was The action of PP has not yet been established al- eliminated by hexamethonium. Adrenergic alpha and though PP has been shown to affect many gastrointesti- beta blockade did not influence the release of PP in it PP response to vagal stimulation. (c) Acetylcholine stimu- nal functions (5). At present seems likely that acts lated, in a dose-dependent manner, the secretion of PP on the exocrine pancreatic tissue as a local regulator of from the isolated perfused porcine pancreas, half-maxi- secretion, in a way that may be conceived as an anti- mal effective dose being 0.19 ,uM; maximal PP output cholecystokinin and secretin-enhancing action (6, 7). in response to 5 min stimulation was 228 pmol, range It has recently been suggested that PP may also affect = satiety (8). 140-342 pmol, n 5. Atropine completely abolished During a meal PP concentrations in plasma increase this response. rapidly (9-13). The fool-mediated PP response consists The results of the present study together with the of a rapid primary phase (5-30 min) which is elimi- previously demonstrated poor PP response to food in nated by truncal vagotomy (10) and a prolonged sec- vagotomized patients, indicate that vagal, cholinergic ondary phase (0.5-6 h) which in man is reduced but stimulation is a major regulator of PP secretion. not abolished by vagotomy (10). The present study was This work was presented in part at the 11th Acta Endo- undertaken to investigate the effect of efferent para- crinologica Congress, 20-23 June 1977, Lausanne, Switzer- sympathetic stimulation on PP secretion. land, Abstract 161. 1977. Acta Endocritnol. 212 (Suppl.): 106. (Abstr.) ' Abbreviationis used in this paper: DU, duodenal ulcer; PP, Received for publication 18 Jtuly and in revised form 25 panereatic poly-peptides; VIP, vasoactive intestinal polypep- October 1977. tide. The Jouirnal of Clinical Investigation Volunme 61 March 1978 781-789 781 MIETHODS tweeni-assay coefficient of variation tested in 10 consecutive assays at concentrations of 30 and 75'pM was 12.8 and 12.1%. Radioimnmu noassay for paticreatic polypeptide Accuracy. Measurements of PP in plasma with added PP, and in dilutions of perfusate from the isolated panicreas (see Anitiserum. Anti-PP serumll (146-5), at generouis gift from below), porcine plasma, and human plasmla yielded results Drs. R. E. Chance and N. E. Moon (Eli Lilly & Co., Indianap- which deviated <20% from the expected values. The follow- olis, Ind.), was raised in a rabbit against subcutaneously in- ing specimens were exposed to gel permeation chromiiatog- jected highly purified bovine PP (BPP) coupled to albumin raphy: (a) perfusate from the isolated porcine pancreas during and mixed with complete Freund's adjuvant. The anltiserum stimulation with acetylcholinie; (b) porcine plasma obtained was used at a final dilution of 1/7.5 x 106. from the portal vein during electrical stimulation of the vagus Tracer. HighlyIpurified bovine PP was iodinlated by a nerve; and (c) human plasma obtained during in.sulini hypo- chloramine T method: 1 mCi 1251 (Behrinig-Werke AG, Mar- glycenmia. The gel permeation chromatography was performed burg/LLahi, West Germclany), 0.24 numlol (1 ,ug) highly pturified at 4°C on 10 x 1,000 mm Sephadex G-5( superfine columns BPP (a gift from Dr. Chance, Eli Lilly & Co.), and 18 nmol eluted with 1.0 M acetic acid with 2% equine serum and 0.2% (5 ,g) chloramine T was mixed in a total volume of 0.023 ml/ bovine serumii albumin. The fractions were lvophilize(d and 0.05 M sodium phosphate buffer, pH 7.4. The reactioni was reconstituted in barbitonie buffer 0.02 M, pH 8.4. In everv case terminated after 20 s by the addition of 26 nmol (5 ,ug) sodiun only one major immunoreactive peak with elution position metabisulfite in 0.010 ml sodium phosphate buffer. Theni 1.2 corresponding to purified PP was found, Fig. 1. Wheni plasma gnmol of potassium iodide in 0.1 nl wvas added followed by 0.2 ml of equine serum. The tracer was purifiedl on a 10 x 1,00( mm Sephadex G-50 superfine columni eluted with amlnmonium bicarbonate,(0.25 Xi, pH 8.2, at 4°C. The fractioins froml the 200- A ascending part of the 1251_PP peak gave the lowest unspecific binding without antibody (1-3%) and the highest binding in antibody surplus (90-95%). The specific radioactivity of the 150 - tracer was calculated to 200-250 /.Ci/4g (0.8-1.05 x 106 Ci/ m10ol). Standard. Highly purifiedl humclan PP (a gift from Dr. 100 - Chance, Eli Lilly & Co.) was usedl as standard. x in so- Assaly condition.s. Incubation was carriedl oUt 0.02 E dium barbitonie buffer, pH 8.4, with 0.2% bovine serumii al- 0C 50 - bumin (Ortho Pharmaceutical Corp., Raritani, N. J.) and 0.6 mnM thiomersal. The incubationi volume was 1.5 ml. In assays w 0- of plasma the saimple volume comprised 1/20 of the incubation UJQ- volume and in other assays at most 1/10 of the incubation CL volume. To obtain comparable incubation coniditions "hor- B mnone-free" plasma, twice treated with charcoal, was added to -J the standard and the same volume of buffer was added to the 0 50 - plasmiia samples. Incubation for 3 days was used in all assays a. except in assays on column eluates, where preincubation for 0 2 days was followed by 1 day of incuibation with tracer. 25 - Separation. Separation was performed with plasma- w Ir coated charcoal (Merck article 2186, Merck AG, Darmstadt, 0 West Germany). To each tube 0.5 ml of a preincubated char- z 0- coal slurry, 0.25 ml charcoal 40 g/liter and 0.25 ml outdated 0L plasma, was added.
Load more

Recommended publications
  • Different Mechanisms of Calcitonin, Calcitonin Gene-Related Peptide
    Henry Ford Hospital Medical Journal Volume 35 Number 2 Second International Workshop on Article 20 MEN-2 6-1987 Different Mechanisms of Calcitonin, Calcitonin Gene-Related Peptide, and Somatostatin Regulation by Glucocorticoids in a Cell Culture of Human Medullary Thyroid Carcinoma Gilbert J. Cote Robert F. Gagel Follow this and additional works at: https://scholarlycommons.henryford.com/hfhmedjournal Part of the Life Sciences Commons, Medical Specialties Commons, and the Public Health Commons Recommended Citation Cote, Gilbert J. and Gagel, Robert F. (1987) "Different Mechanisms of Calcitonin, Calcitonin Gene-Related Peptide, and Somatostatin Regulation by Glucocorticoids in a Cell Culture of Human Medullary Thyroid Carcinoma," Henry Ford Hospital Medical Journal : Vol. 35 : No. 2 , 149-152. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol35/iss2/20 This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Different Mechanisms of Calcitonin, Calcitonin Gene-Related Peptide, and Somatostatin Regulation by Glucocorticoids in a Cell Culture of Human Medullary Thyroid Carcinoma Gilbert J. Cote, and Robert F. Gagel* We have employed the TT cell line, a model for the human medullary thyroid carcinoma cell, lo study the regulation of peptide hormone production by glucocorticoids. Complementary DNA probes were used to measure the calcitonin (CT), CT gene-related peptide (CGRP), and somatostatin (SRIF) mRNA levels. Dose-response experiments in serum-free medium showed that dexamethasone (six-day treatment) lowered somatostatin (to 1% of basal) and CGRP mRNA (to 50% of basal) and stimulated CT mRNA (threefold to thirteenfold) with a half-maximal effective concentration of 10 " M.
    [Show full text]
  • Mechanisms of Hormone Action: Peptide Hormones
    Frontiers in Reproductive Endocrinology Serono Symposia International Mechanisms of Hormone Action: Peptide Hormones Kelly Mayo Northwestern University Mechanisms of Cell Communication Endocrine Signaling Paracrine Signaling Autocrine Juxtacrine Signaling Signaling Endocrine Signaling 1 Emergence of Key Concepts in Hormone Action Berthold, 1849 Starling, 1905 Castrated cockerels and Stimulation of pancreatic restored male sex enzyme secretion by characteristics by replacing humoral factor (secretin) testes in the abdomen from intestinal extracts “Endocrinology” “Hormone” Langley, 1906 Sutherland, 1962 Action of nicotine and Glycogen metabolism and curare on the ‘receptive hormonal activation of substance’ of the liver phosphorylase neuromuscular junction enzyme by cAMP “Receptor” “Second Messenger” Structural Diversity in Reproductive Hormonal Signaling Molecules pyroGlu His Trp Ser HOOC OH Tyr Gly OH Leu N O Arg HO H Pro O OH Gly GlyNH2 FSH GnRH Estradiol PGF2a Nitric Oxide Protein Peptide Steroid Eicosanoid Gas 203 aa 10 aa MW 272 MW 330 MW 30 2 Measuring Receptor-Ligand Interaction ka R (receptor) + H (hormone)! ! RH (complex) Total Binding kd Specific Binding Ka = [RL] Kd = [R][L] ! [R][L] ! [RL] (units are moles -1) (units are moles) Nonspecific Binding Fractional Binding Total R, RT= [R] + [RL], so: Kd = [RT-RL][L] [Hormone] [RL] Rearrange to: [L] = [RL](Kd + [L] [RT] ~Kd Fraction of receptor [RL] = [L] = 1 ocupied by ligand: [RT] Kd + [L] 1 + Kd ! ! ! ! [L] Fractional Binding At 50% occupancy (1/2), Kd = [L] log [Hormone] General
    [Show full text]
  • Pancreatic Polypeptide — a Postulated New Hormone
    Diabetologia 12, 211-226 (1976) Diabetologia by Springer-Verlag 1976 Pancreatic Polypeptide - A Postulated New Hormone: Identification of Its Cellular Storage Site by Light and Electron Microscopic Immunocytochemistry* L.-I. Larsson, F. Sundler and R. H~ikanson Departments of Histology and Pharmacology, University of Lund, Lund, Sweden Summary. A peptide, referred to as pancreatic Key words: Pancreatic hormones, "pancreatic polypeptide (PP), has recently been isolated from the polypeptide", islet cells, gastrointestinal hormones, pancreas of chicken and of several mammals. PP is immunocytochemistry, fluorescence histochemistry. thought to be a pancreatic hormone. By the use of specific antisera we have demonstrated PP im- munoreactivity in the pancreas of a number of mam- mals. The immunoreactivity was localized to a popula- tion of endocrine cells, distinct from the A, B and D While purifying chicken insulin Kimmel and co- cells. In most species the PP cells occurred in islets as workers detected a straight chain peptide of 36 amino well as in exocrine parenchyma; they often predomi- acids which they named avian pancreatic polypeptide nated in the pancreatic portion adjacent to the (APP) [1, 2]. By radioimmunoassay APP was de- duodenum. In opossum and dog, PP cells were found tected in pancreatic extracts from a number of birds also in the gastric mucosa. In opossum, the PP cells and reptiles, and was found to circulate in plasma displayed formaldehyde- induced fluorescence typical where its level varied with the prandial state [3]. From of dopamine, whereas no formaldehyde-induced mammalian pancreas Chance and colleagues isolated fluorescence was detected in the PP cells of mouse, rat peptides that were very similar to APP [see 4].
    [Show full text]
  • Metals Influence C-Peptide Hormone Related to Insulin 17 May 2019, by Andy Fell
    Metals influence C-peptide hormone related to insulin 17 May 2019, by Andy Fell in the body. "A metal is an ingredient—what you do with it is what makes the difference," Heffern said. Her laboratory at UC Davis is using new techniques to understand how metals are distributed inside and outside cells, how they bind to proteins and other molecules and the subtle influences they have on those molecules. The new study looked at C-peptide, or connecting peptide, a short chain of amino acids. C-peptide is being investigated for potential in treating kidney disease and nerve damage in diabetes, so any better understanding of how it behaves in different conditions could be useful in drug development. UC Davis chemist Marie Heffern is pioneering a new field, metalloendocrinology, exploring how metals such Influencing shape and uptake by cells as iron, zinc and copper influence hormones. Credit: Gregory Urquiaga/UC Davis When the pancreas makes insulin, C-peptide connects two chains of insulin in a preliminary step. C-peptide is then cut out, stored along with insulin and released at the same time. C-peptide used to Metals such as zinc, copper and chromium bind to be considered a byproduct of insulin production but and influence a peptide involved in insulin now scientists know that it acts as a hormone in its production, according to new work from chemists own right. at the University of California, Davis. The research is part of a new field of "metalloendocrinology" that The researchers measured how readily zinc, takes a detailed look at the role of metals in copper and chromium bound to C-peptide in test biological processes in the body.
    [Show full text]
  • Insulin and Leptin As Adiposity Signals
    Insulin and Leptin as Adiposity Signals STEPHEN C. BENOIT,DEBORAH J. CLEGG,RANDY J. SEELEY, AND STEPHEN C. WOODS Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio 45267 ABSTRACT There is now considerable consensus that the adipocyte hormone leptin and the pancreatic hormone insulin are important regulators of food intake and energy balance. Leptin and insulin fulfill many of the requirements to be putative adiposity signals to the brain. Plasma leptin and insulin levels are positively correlated with body weight and with adipose mass in particular. Furthermore, both leptin and insulin enter the brain from the plasma. The brain expresses both insulin and leptin receptors in areas important in the control of food intake and energy balance. Consistent with their roles as adiposity signals, exogenous leptin and insulin both reduce food intake when administered locally into the brain in a number of species under different experimental paradigms. Additionally, central administration of insulin antibodies increases food intake and body weight. Recent studies have demonstrated that both insulin and leptin have additive effects when administered simulta- neously. Finally, we recently have demonstrated that leptin and insulin share downstream neuropep- tide signaling pathways. Hence, insulin and leptin provide important negative feedback signals to the central nervous system, proportional to peripheral energy stores and coupled with catabolic circuits. I. Overview When maintained on an ad libitum diet, most animals — including humans — are able to precisely match caloric intake with caloric expenditure, resulting in relatively stable energy stores as adipose tissue (Kennedy, 1953; Keesey, 1986). Growing emphasis has been placed on the role of the central nervous system (CNS) in controlling this precision of energy homeostasis.
    [Show full text]
  • Chemistry of Pancreatic Polypeptide Hormone with Official Preparation
    wjpmr, 2020,6(9), 102-114 SJIF Impact Factor: 5.922 WORLD JOURNAL OF PHARMACEUTICAL Review Article Arpan et al. World Journal of Pharmaceutical and Medical Research AND MEDICAL RESEARCH ISSN 2455-3301 www.wjpmr.com Wjpmr CHEMISTRY OF PANCREATIC POLYPEPTIDE HORMONE WITH OFFICIAL PREPARATION Arpan Chanda*1, Arunava Chandra Chandra2, Dr. Dhrubo Jyoti Sen2 and Dr. Dhananjoy Saha3 1Department of Pharmaceutical Chemistry, Netaji Subhas Chandra Bose Institute of Pharmacy, Roypara, Chakdaha Dist–Nadia, Pin‒741222, West Bengal, India. 2Department of Pharmaceutical Chemistry, School of Pharmacy, Techno India University, Salt‒Lake City, Sector‒V, EM‒4, Kolkata‒700091, West Bengal, India. 3Deputy Director of Technical Education, Directorate of Technical Education, Bikash Bhavan, Salt Lake City, Kolkata‒700091, West Bengal, India. *Corresponding Author: Arpan Chanda Department of Pharmaceutical Chemistry, Netaji Subhas Chandra Bose Institute of Pharmacy, Roypara, Chakdaha Dist–Nadia, Pin‒741222, West Bengal, India. Article Received on 05/07/2020 Article Revised on 26/07/2020 Article Accepted on 16/08/2020 ABSTRACT Insulin which is a peptide hormone is produced by β‒cells of the pancreatic islets and it is considered to be the main anabolic hormone of the body. It further regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of glucose from the blood into liver, fat and skeletal muscle cells. In these tissues the absorbed glucose from the blood is thus converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver both glycogenesis and lipogenesis. Glucose production and secretion by the liver is strongly supported by high concentrations of insulin in the blood.
    [Show full text]
  • Prolactin-Releasing Peptide: Physiological and Pharmacological Properties
    International Journal of Molecular Sciences Review Prolactin-Releasing Peptide: Physiological and Pharmacological Properties Veronika Pražienková 1, Andrea Popelová 1, Jaroslav Kuneš 1,2 and Lenka Maletínská 1,* 1 Biochemistry and Molecular Biology, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences 16610 Prague, Czech Republic; [email protected] (V.P.); [email protected] (A.P.); [email protected] (J.K.) 2 Experimental Hypertension, Institute of Physiology of the Czech Academy of Sciences, 14200 Prague, Czech Republic * Correspondence: [email protected]; Tel.: +420-220-183-567 Received: 2 October 2019; Accepted: 23 October 2019; Published: 24 October 2019 Abstract: Prolactin-releasing peptide (PrRP) belongs to the large RF-amide neuropeptide family with a conserved Arg-Phe-amide motif at the C-terminus. PrRP plays a main role in the regulation of food intake and energy expenditure. This review focuses not only on the physiological functions of PrRP, but also on its pharmacological properties and the actions of its G-protein coupled receptor, GPR10. Special attention is paid to structure-activity relationship studies on PrRP and its analogs as well as to their effect on different physiological functions, mainly their anorexigenic and neuroprotective features and the regulation of the cardiovascular system, pain, and stress. Additionally, the therapeutic potential of this peptide and its analogs is explored. Keywords: prolactin-releasing peptide; GPR10; RF-amide peptides; food intake regulation; energy expenditure; neuroprotection; signaling 1. Introduction There is no doubt that the function of prolactin-releasing peptide (PrRP) in organisms is quite important as its structure is well conserved within different animal species.
    [Show full text]
  • The Peptide Hormone Cholecystokinin Links Obesity To
    Published OnlineFirst May 1, 2020; DOI: 10.1158/2159-8290.CD-RW2020-065 RESEARCH WATCH Pancreatic Cancer Major Finding: Beta-cell cholecystokinin Concept: Early weight loss in this Impact: This study mechanistically expression in obese mice promoted pan- mouse model suppressed tumorigene- links obesity to PDAC and suggests creatic ductal adenocarcinoma (PDAC) . sis, but later-stage weight loss did not . when intervention may be effective . THE PEPTIDE HORMONE CHOLECYSTOKININ LINKS OBESITY TO PANCREATIC CANCER Obesity is a contributor to pancreatic ductal ade- tions in the fi broinfl ammatory microenvironment nocarcinoma (PDAC), but the mechanisms under- were not causative in PDAC development could not lying this phenomenon are not fully established. be ruled out. Interestingly, although pancreatic islets Furthermore, it is unclear whether or at what point showed evidence of obesity-induced adaptation, during PDAC development weight-loss interven- increased insulin levels or insulin signaling did not tions may be benefi cial. To investigate this, Chung, appear to be to blame for the increase in tumorigen- Singh, Lawres, Dorans, and colleagues developed esis in obese mice. Instead, upregulation of the pep- an autochthonous mouse model of Kras-mutant, tide hormone cholecystokinin (CCK) by beta cells genetically obesity-driven PDAC. These mice exhibited early- in obese mice was observed to promote PDAC development, onset ob esity due to leptin defi ciency and had more rapid PDAC and increased obesity in humans without known malignancy progression
    [Show full text]
  • 60 YEARS of POMC: POMC: the Consummate Peptide Hormone
    56:4 A J L CLARK and P LOWRY 60 years of POMC 56:4 E1–E2 Editorial 60 YEARS OF POMC POMC: the consummate peptide hormone precursor Correspondence Adrian J L Clark1 and Philip Lowry2 should be addressed to A J L Clark or P Lowry 1Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, Email London, UK [email protected] or 2Emeritus Professor School of Biological Sciences, The University of Reading, Reading, UK [email protected] Proopiomelanocortin (POMC) has been at the forefront peptidylglycine α-amidating monooxygenase enzymes of molecular endocrinology for the past 60 years, and the whose far wider role continues to be an active area of concepts derived from POMC research have led the way research and is reviewed by Dhivya Kumar and colleagues in understanding a wide range of endocrine systems. In (Kumar et al. 2016). The subsequent trafficking, sorting, this issue, we celebrate this enormous body of work with and storage of POMC products before secretion has also contributions from an outstanding faculty of contributors, contributed significantly to our knowledge of the broader many of whom have led these discoveries. The story aspects of this process and is reviewed by Peng Loh and begins approximately 60 years ago when Li and colleagues colleagues (Cawley et al. 2016). reported purifying and sequencing ACTH (Li et al. 1955, Cloning of the POMC gene confirmed the Dixon & Li 1956). They and others subsequently reported highly tissue-specific nature of its expression and purification ofα - and β-MSH; however, it was with the simultaneously revealed the nature of its promoter.
    [Show full text]
  • A Peptide-Hormone-Inactivating Endopeptidase in Xenopus Laevis Skin Secretion
    Proc. Nati. Acad. Sci. USA Vol. 89, pp. 84-88, January 1992 Biochemistry A peptide-hormone-inactivating endopeptidase in Xenopus laevis skin secretion (metailoendopeptidase/neutral endopeptidase/thermolysin) KRISHNAMURTI DE MORAIS CARVALHO*, CARINE JOUDIOU, HAMADI BOUSSETTA, ANNE-MARIE LESENEY, AND PAUL COHEN Groupe de Neurobiochimie Cellulaire et Moldculaire de l'Universitd Pierre et Marie Curie, Unit6 de Recherche Associ6e 554 au Centre National de la Recherche Scientifique, % Boulevard Raspail, 75006 Paris, France Communicated by I. Robert Lehman, September 16, 1991 ABSTRACT An endopeptidase was isolated from Xenopus Indeed the Ser-Phe dipeptide, or a related motif such as laevis skin secretions. This enzyme, which has an apparent Phe-Phe, Ala-Phe, or His-Phe, is often present near the molecular mass of 100 kDa, performs a selective cleavage at the carboxyl terminus of substances from the bombesin and Xaa-Phe, Xaa-Leu, or Xaa-Ile bond (Xaa = Ser, Phe, Tyr, His, tachykinin families (1). Xaa-Phe, Xaa-Leu, or Xaa-Ile was or Gly) of a number of peptide hormones, including atrial also found frequently at a similar position in other peptide natriuretic factor, substance P, angiotensin H, bradykinin, hormone sequences of higher organisms, notably in atrial somatostatin, neuromedins B and C, and litorin. The peptidase natriuretic factor (ANF). exhibited optimal activity at pH 7.5 and aKm in the micromolar We have purified this enzyme 2029-fold and demonstrate range. No cleavage was produced in vasopressin, ocytocin, that it inactivates ANF by exclusive cleavage of the Ser25- minigastrin I, and [Leu5Jenkephalin, which include in their Phe26 bond and similarly inactivates a number of important sequence an Xaa-Phe, Xaa-Leu, or Xaa-Ile motif.
    [Show full text]
  • Nov 6 Cell Signaling
    Biochem 03 Cell Communication November 6, 2009 Function: Signal Transduction • Steroid Hormones • Long term acting signals • Peptide Hormones • Various modes of action • Second Messengers • IP3 • Ca(II) • Calmodulin Endocrine System • Steroid Hormones • Primary source of these molecules are the ovaries and testes • Peptide Hormones • Primary source for these molecules are the rest of the endocrine system: hypothalmus, pineal, pituitary, thyroid, pancreas Endocrine System Mission Control Anterior Pituitary Posterior Pituitary Most of these are PEPTIDE HORMONES Hormones enter cells through different methods depending on their chemical nature Peptide hormones Steroid hormones Peptide Hormones---Vasopressin • Vasopressin is also known as arginine vasopressin (AVP), and antidiuretic hormone (ADH) • Vasopressin is a peptide hormone that contains just nine amino acids Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly • The precursor protein molecule is 164 amino acids and is made in the hypothalamus • The processes vasopressin is stored in vesicles at the posterior pituitary While most of the vasopressin in the posterior pituitary will be released into the blood stream; some of it is also released directly into the brain Peptide Hormones---Vasopressin Function • Primary role of vasopressin is to regulate the body's retention of water; it is released when the body is dehydrated and causes the kidneys to conserve water, thus concentrating the urine and reducing urine volume • In high concentrations, it also raises blood pressure by inducing moderate vasoconstriction
    [Show full text]
  • (CRH) Requirement in Clostridium Difficile Toxin A-Mediated Intestinal Inflammation
    Corticotropin-releasing hormone (CRH) requirement in Clostridium difficile toxin A-mediated intestinal inflammation Pauline M. Anton*, Jerome Gay†, Andreas Mykoniatis*, Amy Pan*, Michael O’Brien‡, Daniel Brown§, Katia Karalis†, and Charalabos Pothoulakis*¶ *Division of Gastroenterology and §Morphology Core Facility, Beth Israel Deaconess Medical Center, and †Division of Endocrinology, Children’s Hospital, Harvard Medical School, Boston, MA 02115; and ‡Department of Pathology, Mallory Institute, Boston University School of Medicine, Boston, MA 02218 Communicated by Susan E. Leeman, Boston University School of Medicine, Boston, MA, April 16, 2004 (received for review January 10, 2004) Clostridium difficile, the causative agent of antibiotic-associated C. difficile is the primary agent responsible for antibiotic- colitis, mediates inflammatory diarrhea by releasing toxin A, a associated diarrhea and pseudomembranous colitis after antibi- potent 308-kDa enterotoxin. Toxin A-induced inflammatory diar- otic therapy (20). C. difficile causes diarrhea and colitis by rhea involves many steps, including mucosal release of substance releasing two high-molecular-mass protein exotoxins, toxin A P (SP) corticotropin-releasing hormone (CRH) and neutrophil trans- and B, with potent cytotoxic and enterotoxic properties in migration. Here we demonstrate that, compared with wild type, animal and human intestine (21). Injection of toxin A into ileal -mice genetically deficient in CRH (Crh؊/؊) have dramatically re- or colonic loops of anesthetized animals triggers
    [Show full text]