Gastrointestinal Regulatory Peptides

462 Pages·1993·11.745 MB·English

by  F. Sundler, E. Ekblad, R. Håkanson (auth.), David R. Brown Ph.D. (eds.)

Handbook of
Experimental Pharmacology
Volume 106
Editorial Board
G.V.R. Born, London
P. Cuatrecasas, Ann Arbor, MI
H. Herken, Berlin
Gastrointestinal
Regulatory Peptides
Contributors
A. Alemayehu, B. Amiranoff, D.L. Barber, S.R. Bloom
J. Calam, R.E. Carraway, Feng Chen, C.S. Chew,
C.C. Chou, J.M. Conlon, A. Couvineau, E. Ekblad,
T.S. Gaginella, J.J. Galligan, J.R. Grider, R. Hakanson
P. Kitabgi, M. Laburthe, Y.P. Loh, M.S. O'Dorisio
S.M. O'Grady, R.K. Pearson, R.J. Playford
E. Rozengurt, F. Sundler, I. Zachary
Editor
David R. Brown
Springer-Verlag
Berlin Heidelberg New York London Paris
Tokyo Hong Kong Barcelona Budapest
DAVID R. BROWN, Ph.D.
Department of Veterinary Biology
Pharmacology Section
University of Minnesota
1988 Fitch Avenue
Saint Paul, MN 55108
USA
With 50 Figures and 20 Tables
ISBN-13: 978-3-642-77816-2 e-ISBN-13: 978-3-642-77814-8
DOl: 10.1007/978-3-642-77814-8
Library of Congress Cataloging-in-Publication Data. Gastrointestinal regulatory peptides / contribu
tors, A. Alemayehu ... [et al.]; editor, David R. Brown. p. cm.-(Handbook of experimental
pharmacology; v. 106) Includes bibliographical references and index. 1. Gastrointestinal hormones.
I. A1emayehu, A. n. Brown, David R. (David Robert), 1954- . III. Series. [DNLM:
1. Gastrointestinal Hormones- physiology. 2. Gastrointestinal System-physiology. 3.
Neuropeptides-pharmacology. 4. Neuro-peptides-physiology. WI HA51L v. 106/ WK 170
G2579] QP905.H3 vol. 106 [QP572.G35] 615' .ls- dc20 [612.3'2] DNLMIDLC for Library of
Congress 92-49563 CIP
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List of Contributors
ALEMAYEHU, A., Department of Physiology, Michigan State University,
East Lansing, MI 48828-1101, USA
AMlRANOFF, B., INSERM U239, Faculte de Medecine Xavier Bichat, 16 rue
H. Huchard, F-75018 Paris, France
BARBER, D.L., Department of Stomatology, School of Dentistry, Division of
Oral Biology, University of California at San Francisco, San Francisco,
CA 94143-0512, USA
BLOOM, S.R., Royal Postgraduate Medical School, Hammersmith Hospital,
Du Cane Road, London W12 ONN, Great Britain
CALAM, J., Royal Postgraduate Medical School, Hammersmith Hospital,
DuCane Road, London W12 ONN, Great Britain
CARRAWAY, R.E., Department of Physiology, University of Massachusetts
Medical Center, 55 Lake Avenue North, Worcester, MA 01655, USA
CHEN, FENG, Departments of Pediatrics and Medical Microbiology and
Immunology, The Ohio State University, 700 Children's Drive, Colum
bus, OH 43205, USA
CHEW, C.S., Department of Physiology, Morehouse School of Medicine,
720 Westview Drive, S.W., Atlanta, GA 30310-1495, USA
CHOU, C.C., Departments of Physiology and Medicine, Michigan State
University, East Lansing, MI 48824-1101, USA
CONLON, J.M., Regulatory Peptide Center, Department of Biomedical
Sciences, Creighton University Medical Center, 2500 California Street,
Omaha, NB 68178, USA
COUVINEAU, A., INSERM U239, Faculte de Medecine Xavier Bichat, 16 rue
H. Huchard, F-75018, France
EKBLAD, E., Department of Medical Cell Research, University of Lund,
Biskopsgatan 5, S-223 62 Lund, Sweden
GAGINELLA, T.S., Gastrointestinal Pharmacology, P.O. Box 1049, Wood
land, CA 95695, USA
VI List of Contributors
GALLIGAN, J.J., Department of Pharmacology and Toxicology, Michigan
State University, Life Sciences Building, Room B-328, East Lansing, MI
48824, USA
GRIDER, J .R., Departments of Physiology and Medicine, Medical College of
Virginia, Box 711, MCV Station, Richmond, VA 23298, USA
HAKANSON, R., Department of Medical Cell Research, University of Lund,
Biskopsgatan 5, S-223 62 Lund, Sweden
KrrABGI, P., Institut de Pharmacologie Cellulaire et Moleculaire du CNRS,
Sophia Antipolis, F-06560 Valbonne, France
LABURTHE, M., INSERM U239, Faculte de Medecine Xavier Bichat, 16 rue
H. Huchard, F-75018 Paris, France
LOH, Y.P., Section on Cellular Neurobiology, Laboratory of Developmental
Neurobiology, National Institute of Child Health and Human Develop
ment, National Institutes of Health, Bethesda, MD 20892, USA
O'DORISIO, M.S., Departments of Pediatrics and Medical Microbiology and
Immunology, The Ohio State University, 700 Children's Drive, Colum
bus, OH 43205, USA
O'GRADY, S.M., Departments of Physiology and Animal Science, University
of Minnesota, 1988 Fitch Avenue, St. Paul, MN 55108, USA
PEARSON, R.K., Center for Basic Research in Digestive Diseases, Mayo
Clinic and Mayo Foundation, 200 First Street, S.W., Rochester, MN
55905, USA
PLAYFORD, R.J., Royal Postgraduate Medical School, Hammersmith
Hospital, DuCane Road, London W12 ONN, Great Britain
ROZENGURT, E., Imperial Cancer Research Fund, Growth Regulation
Laboratory, P.O. Box 123, 44 Lincoln's Inn Fields, London WC2A 3PX,
Great Britain
SUNDLER, F., Department of Medical Cell Research, University of Lund,
Biskopsgatan 5, S-223 62 Lund, Sweden
ZACHARY, I., Imperial Cancer Research Fund, Growth Regulation Labora
tory, P.O. Box 123, 44 Lincoln's Inn Fields, London WC2A 3PX, Great
Britain
Preface
Since the discovery of the pancreatic secretagogue secretin by W.M. BAYLISS
and E.H. STARLING at the inception of the twentieth century, intense interest
has focused on numerous, continually expanding classes of small peptides
which appear to serve as regulatory molecules in the gastrointestinal tract,
brain, and other organ systems. Initially, many of these substances were,
like secretin, discovered in functional assays as "factors" or "activities"
extractable in minute quantities from tissues or tissue fluids. By the middle
of the century, advances in biochemical and immunological methods for the
purification, characterization, and quantification of biologically active
peptides in organ systems, tissues, and body fluids provided further impetus
to this field. It was readily appreciated that small, biologically active
peptides were particularly abundant in the digestive tract. Many peptides
such as vasoactive intestinal peptide, gastrin, and more recently peptide YY
and galanin were in fact originally discovered in and isolated from gut tissue.
Moreover, these peptides were found to have profound actions on the
gastroenteropancreatic system in vivo and in vitro. During the past 2
decades, information on regulatory peptides has burgeoned as a result of
technological refinements in the synthesis of peptides, improved methods for
detecting and visualizing peptides and their precursors in cells and tissues
from a variety of species, advances in the functional assessment of peptide
activity, and the application of molecular biological techniques to the char
acterization of peptide gene structure and expression. It has become clear
that, as a diverse group of molecules present in a variety of cell types, small
peptides are capable of producing a plethora of biological effects and may
subserve roles as hormones, neurotransmitters, paracrine mediators, and
autocrine factors depending upon their cellular location. In addition,
regulatory peptides appear to be associated with aspects of several disease
states and have been used both as diagnostic markers and as therapeutic
agents.
The purpose of this volume of the Handbook of Experimental Pharma
cology is to distill, from the vast amount of information collected on gut
regulatory pep tides , general concepts related to the production, fate, and
actions of gut peptides as viewed primarily from cellular and molecular
perspectives. Although common aspects of gut peptide biology are high
lighted by the use of selected peptides as examples, no attempt was made to
VIII Preface
exhaustively detail the numerous facts available on specific gut peptides or
peptide families. The subject material which follows is at once broad in
scope and comprehensive. It is organized into three sections which develop
in a logical sequence and is sufficiently balanced to interest pharmacologists
and other investigators in a variety of biomedical disciplines. The first six
chapters deal with the localization of pep tides within cells of the gastro
intestinal tract, peptide gene expression, and post-translational processing.
In addition, the cellular release of peptides, subsequent interactions of these
substances with their receptors on target cells, and the role of peptidase
enzymes in terminating peptide action are considered. The next seven
chapters discuss the cellular mechanisms by which peptides act to influence
the function of specific cell types located in the gastrointestinal tract.
Accordingly, the possible roles and pharmacological effects of peptides in
such seemingly diverse functions as gastric acid secretion, the activity of
enteric neurons, the contractility of gut smooth muscle, active ion transport
in intestinal epithelial cells, intestinal blood flow, cellular growth and
proliferation, and mucosal immunity are reviewed. The final two chapters
focus on the known and suggested roles of peptides in disease states involv
ing the digestive tract as well as the potential importance of these bio
logically active substances and their antagonists as drugs. It is hoped that
this book will serve as an important, one-volume reference source for new
and continuing investigations on the biology of regulatory peptides in the
gastrointestinal tract and other organ systems well into the next century.
I am exceedingly grateful to all of the distinguished investigators who
have authored chapters in this volume. They are to be highly commendeq,
not only for their punctuality, which greatly facilitated the publication
process, but for their uniformly excellent contributions which met and in
many cases surpassed my expectations. Moreover, I thank the members of
the Handbook's Editorial Board for the opportunity to serve as Editor of
this prestigious volume, and Ms. DORIS WALKER for her assistance in the
publishing process. Finally, I am indebted to my wife, Dr. LAURA J. MAURO,
for her encouragement and loving support in the preparation of this book.
DAVID R. BROWN
Contents
CHAPTER 1
Localization and Colocalization of Gastrointestinal Peptides
F. SUNDLER, E. EKBLAD, and R. HAKANSON. With 10 Figures 1
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
B. Coexistence of Messengers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
C. Endocrine and Paracrine Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
I. Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
II. Small Intestine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
III. Large Intestine ...................................... 8
IV. Coexistence of Peptides in Gut Endocrine Cells .......... 8
D. Enteric Neurons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
I. Distribution of Peptide-Containing Nerve Fibers
in the Digestive Tract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
II. Projections of Enteric Neurons in the Rat . . . . . . . . . . . . . . . 16
1. Myenteric Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2. Submucous Neurons... . . .. . . . . . . . . .. . . . . .. ... . . . . . 17
III. Coexistence of Peptides in Enteric Neurons. . . . . . . . . . . . . . 18
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
CHAPTER 2
Regulation of Gastrointestinal Peptide Hormone Gene Expression
R.K. PEARSON. With 5 Figures .............................. '.',' . 29
A. Introduction.............................................. 29
B. Gene Structure ............. .-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
C. RNA Polymerase II ................... " . . . . . . . . . . . . .. . . .. . 31
D. Transcriptional Regulation Overview. . . . . . . . . . . . . . . . . . . . . . . . . 33
I. DNA Elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
II. Transcription Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
1. General Transcription Factors. . . . . . . . . . . . . . . . . . . . . . . 35
2. Regulated Transcription Factors. . . . . . . . . . . . . . . . . . . . . 35
3. Modulation of Transcription Factor Activity. . . . . . . . . . . 38
x Contents
III. Transcriptional Repression . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
IV. Genes Lacking TATA Elements ....................... 44
E. Analysis of Gene Expression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
I. RNA Quantitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
II. Promoter Studies .................................... 45
F. Regulation of Specific Hormone Gene Expression. . . .. . . .. . . . . . 48
I. Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
II. Gastrin/Cholecystokinin Family. . . . . . . . . . . . . . . . . . . . . . . . 48
1. Gastrin: Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
2. Luminal Regulation of Gastrin Gene Expression. . . . . . . 49
3. Islet Cell Gastrin Expression. . . . . . . . . . . . . . . . . . . . . . . . 50
4. Gastrin Promoter Analysis. . . . . . . . . . . .. . . . . . . .. . . . . . 51
a) Studies in Pituitary Cell Lines . . . . . . . . . . . . . . . . . . . . 52
b) Studies in Islet Cells ............................ 53
5. Cholecystokinin: Background. . . . . . . . . . . . . . . . .. . . . . . 53
6. Cholecystokinin Gene Regulation: RNA Quantitation . . 54
7. Cholecystokinin: Promoter Analysis ................. 55
III. Somatostatin ........................................ 56
1. Somatostatin Gene Regulation . . . . . . . . . . . . . . . . . . . . . . 56
2. Model of cAMP Regulation. . . . . . . . . . . . . . . . . . . . . . . . . 57
3. Tissue Specific Expression. . . . . . . . . . . . . . . . . . . . . . . . . . 58
IV. Glucagon........................................... 59
V. Secretin............................................. 60
VI. Motilin ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
G. Conclusion ............................................... 61
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
CHAPTER 3
Post-Translational Processing of Regubltory Peptides
R.E. CARRAWAY and Y.P. LOH. With 4 Figures.................... 69
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
B. General Design of Processing Systems . . . . . . . . . . . . . . . . . . . . . . . . 69
I. Active Peptide Stored in Secretory Vesicles. . . . . . . . . . . . . . 70
II. Active Peptide Released Constitutively ................. 72
III. Precursor Activated in or Near Cell of Origin . . . . . . . . . . . . 73
1. Precursor Stored Intracellularly ..... ,............... 73
2. Precursor Anchored to Cell Surface. . . . . . . . . . . . . . . . . . 74
IV. Precursor Activated in the Interstitial Space or Blood. . . . . 75
V. Precursor Activated at Target or by Other Cells . . . . . . . . . . 77
1. Precursor Stored Outside Target. . . . . . . . . . . . . . . . . . . . . 78
2. Precursor Stored Inside Target . . . . . . . . . . . . . . . . . . . . . . 78
VI. Mixed Systems.................................. . . ... 79
C. Intracellular Trafficking and Processing Pathways . . . . . . . . . . . . . . 80
Contents XI
D. Processing Sites and General Mechanisms. . . . . . . . . . . . . . . . . . . . . 81
I. Two-Step Processing ................................. 81
II. Dibasic, Monobasic and Nonbasic Sites ................. 81
III. Conformation and Consensus Features. . . . . . . . . . . . . . . . . . 81
IV. Sequentially Ordered Reactions. . . . . . . . . . . . . . . . . . . . . . . . 82
V. Tissue-Specific Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
E. Enzymes Involved in the Processing of Prohormones ........... 83
I. Dibasic Residue-Specific Endoproteases . . . . . . . . . . . . . . . . . 83
II. Monobasic Residue-Specific Endoproteases . . . . . . . . . . . . . . 86
III. Tetrabasic Residue-Specific Endoproteases . . . . . . . . . . . . . . 86
IV. Exopeptidases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
V. Enzymes Involved in N- and C-Terminal Modification. . . . . 88
1. Acetyltransferase.................................. 88
2. Glutaminyl Cyclase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
3. Peptidylglycine a-Amidating Monooxygenase ......... 89
VI. Enzymes Involved in Sulfation and Phosphorylation ...... 90
1. Tyrosine Sulfation Enzyme ......................... 90
2. Serine Phosphorylating Enzymes .................... 90
F. Processing of Specific Prohormones . . . . . . . . . . . . . . . . . . . . . . . . . . 91
I. Yeast Pheromones ................................... 91
II. Proopiomelanocortin ............................... . . 92
III. Gastrointestinal Hormones. . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
1. Glucagon and Related Peptides ..................... 93
2. Cholecystokinin................................... 94
3. Gastrin .......................................... 94
4. Somatostatin...................................... 95
5. Neurotensin and Neuromedin-N . . . . . . . . . . . . . . . . . . . . . 95
6. Pancreatic Polypeptide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
G. Conclusion ............................................... 96
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
CHAPTER 4
Regulation of Peptide Secretion from Gastroenteric Endocrine Cells
D.L. BARBER. With 7 Figures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
B. Gastroenteric Endocrine Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
I. Localization......................................... 105
II. Methods for Studying Peptide Release. . . . . . . . . . . . . . . . . . 106
C. Neurotransmitter and Peptide Regulation of Release. . . . . . . . . . . 108
I. Acetylcholine........................................ 108
II. Norepinephrine............... . . . . . . . . . . . . . . . . . . . . . . . 111
III. Somatostatin........................................ 112
IV. Gastrin-Releasing Peptide and Bombesin. . . . . . . . . . . . . . . . 115