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Vol. 52, Issue 2, 269-324, June 2000
Institut Fédératif de Recherches Multidisciplinaires
sur les Peptides (IFRMP 23), Laboratoire de Neuroendocrinologie
Cellulaire et Moléculaire, Institut National de la Santé et
de la Recherche Médicale U413, Unité Affiliée au Centre
National de la Recherche Scientifique, Université de Rouen,
Mont-Saint-Aignan, France (D.V., B.J.G., M.B., L.Y., H.V.); and
Institut National de la Recherche Scientifique-Institut Armand
Frappier, Université du Québec, Pointe-Claire, Canada
(A.F.)
I. Introduction
II. PACAP
A. Discovery of PACAP
B. Secondary Structure of PACAP
C. Structure of the PACAP Precursor and Post-Translational
Processing
D. The PACAP Gene
E. Distribution of PACAP in the CNS
F. Distribution of PACAP in Peripheral Organs
G. PACAP in Tumor Cells
H. Ontogenesis of PACAP
I. Phylogenetic Evolution of PACAP
III. The PACAP Receptors
A. Pharmacological Characterization of PACAP Receptors
B. Biochemical Characterization of PACAP Receptors
C. Cloning of PACAP Receptors
D. Structure-Activity Relationships
E. Distribution of PACAP Receptors in the CNS
F. Distribution of PACAP Receptors in Peripheral Organs
G. PACAP Receptors in Tumor Cells
H. Ontogenesis of PACAP Receptors
I. Phylogenetic Evolution of PACAP Receptors
IV. Biological and Pharmacological Effects of PACAP
A. Effects of PACAP on the CNS
1. Actions on the hypothalamus.
2. Actions of PACAP on the pineal gland.
3. Behavioral actions.
4. Neurotrophic actions.
5. Actions on glial cells.
B. Effects of PACAP on the Pituitary Gland
Gonadotrope cells.
Somatotrope cells.
Lactotrope cells.
Corticotrope cells.
Thyrotrope cells.
FS cells.
Pituitary fibroblasts.
Melanotrope cells.
C. Effects of PACAP on the Thyroid Gland
D. Effects of PACAP on the Gonads
E. Effects of PACAP on the Adrenal Gland
F. Effects of PACAP on the Gastrointestinal Tract
G. Effects of PACAP on the Liver
H. Effects of PACAP on the Pancreas
I. Effects of PACAP on the Respiratory System
J. Effects of PACAP on the Cardiovascular System
K. Effects of PACAP on Immune Cells
L. Effects of PACAP on Bones
M. Effects of PACAP on Tumor Cells
V. Conclusion and Perspectives
Acknowledgments
References
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid peptide that was first isolated from ovine hypothalamic extracts on the basis of its ability to stimulate cAMP formation in anterior pituitary cells. PACAP belongs to the vasoactive intestinal polypeptide (VIP)-glucagon-growth hormone releasing factor-secretin superfamily. The sequence of PACAP has been remarkably well conserved during the evolution from protochordate to mammals, suggesting that PACAP is involved in the regulation of important biological functions. PACAP is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, and respiratory and urogenital tracts. Characterization of the PACAP precursor has revealed the existence of a PACAP-related peptide whose activity remains unknown. Two types of PACAP binding sites have been characterized. Type I binding sites exhibit a high affinity for PACAP and a much lower affinity for VIP whereas type II binding sites have similar affinity for PACAP and VIP. Molecular cloning of PACAP receptors has shown the existence of three distinct receptor subtypes, the PACAP-specific PAC1 receptor, which is coupled to several transduction systems, and the two PACAP/VIP-indifferent VPAC1 and VPAC2 receptors, which are primarily coupled to adenylyl cyclase. PAC1 receptors are particularly abundant in the brain and pituitary and adrenal glands whereas VPAC receptors are expressed mainly in the lung, liver, and testis. The wide distribution of PACAP and PACAP receptors has led to an explosion of studies aimed at determining the pharmacological effects and biological functions of the peptide. This report reviews the current knowledge concerning the multiple actions of PACAP in the central nervous system and in various peripheral organs including the endocrine glands, the airways, and the cardiovascular and immune systems, as well as the different effects of PACAP on a number of tumor cell types.
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M. CIARLO, F. BRUZZONE, C. ANGELINI, D. ALEXANDRE, Y. ANOUAR, M. VALLARINO, and H. VAUDRY Expression of PACAP Receptors in the Frog Brain during Development Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 201 - 204. [Abstract] [Full Text] [PDF]
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B. M. GIRARD, B. A. YOUNG, T. R. BUTTOLPH, S. L. WHITE, and R. L. PARSONS Modulation of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Expression in Explant-Cultured Guinea Pig Cardiac Neurons Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 298 - 302. [Abstract] [Full Text] [PDF]
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E. GONZALEZ-REY, A. CHORNY, and M. DELGADO VIP: An Agent with License to Kill Infective Parasites Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 303 - 308. [Abstract] [Full Text] [PDF]
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I. HARFI and E. SARIBAN Mechanisms and Modulation of Pituitary Adenylate Cyclase-Activating Protein-Induced Calcium Mobilization in Human Neutrophils Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 322 - 329. [Abstract] [Full Text] [PDF]
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M. HIROSE, H. HASHIMOTO, J. IGA, N. SHINTANI, M. NAKANISHI, N. ARAKAWA, T. SHIMADA, and A. BABA Inhibition of Self-Renewal and Induction of Neural Differentiation by PACAP in Neural Progenitor Cells Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 342 - 347. [Abstract] [Full Text] [PDF]
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R. JOZSA, T. HOLLOSY, J. NEMETH, A. TAMAS, A. LUBICS, B. JAKAB, A. OLAH, A. ARIMURA, and D. REGLODI Presence of PACAP and VIP in Embryonic Chicken Brain Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 348 - 353. [Abstract] [Full Text] [PDF]
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A. LEBON, D. SEYER, P. COSETTE, L. COQUET, T. JOUENNE, P. CHAN, J. LEPRINCE, A. FOURNIER, H. VAUDRY, B. J GONZALEZ, et al. Identification of Proteins Regulated by PACAP in PC12 Cells by 2D Gel Electrophoresis Coupled to Mass Spectrometry Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 380 - 387. [Abstract] [Full Text] [PDF]
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C. MARTINEZ, A. ARRANZ, Y. JUARRANZ, C. ABAD, M. GARCIA-GOMEZ, F. ROSIGNOLI, J. LECETA, and R. P. GOMARIZ PAC1 Receptor: Emerging Target for Septic Shock Therapy Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 405 - 410. [Abstract] [Full Text] [PDF]
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O. MASMOUDI-KOUKI, P. GANDOLFO, J. LEPRINCE, D. VAUDRY, G. PELLETIER, A. FOURNIER, H. VAUDRY, and M.-C. TONON PACAP Stimulates Biosynthesis and Release of Endozepines from Rat Astrocytes Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 411 - 416. [Abstract] [Full Text] [PDF]
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K. MATSUDA, K. MARUYAMA, T. NAKAMACHI, T. MIURA, and S. SHIODA Effects of Pituitary Adenylate Cyclase-Activating Polypeptide and Vasoactive Intestinal Polypeptide on Food Intake and Locomotor Activity in the Goldfish, Carassius auratus Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 417 - 421. [Abstract] [Full Text] [PDF]
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L. MOLNAR, E. POLLAK, A. BOROS, D. REGLODI, A. TAMAS, I. LENGVARI, A. ARIMURA, and A. LUBICS Comparative Anatomy of PACAP-Immunoreactive Structures in the Ventral Nerve Cord Ganglia of Lumbricid Oligochaetes Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 427 - 430. [Abstract] [Full Text] [PDF]
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C. MORETTI, C. MAMMI, G. V. FRAJESE, S. MARIANI, L. GNESSI, M. ARIZZI, F. WANNENES, and G. FRAJESE PACAP and Type I PACAP Receptors in Human Prostate Cancer Tissue Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 440 - 449. [Abstract] [Full Text] [PDF]
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Y. MORITA, D. YANAGIDA, N. SHINTANI, K. OGITA, N. NISHIYAMA, R. TSUCHIDA, H. HASHIMOTO, and A. BABA Lack of Trimethyltin (TMT)-Induced Elevation of Plasma Corticosterone in PACAP-Deficient Mice Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 450 - 456. [Abstract] [Full Text] [PDF]
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L. MOUNIEN, P. BIZET, I. BOUTELET, G. GOURCEROL, M. BASILLE, B. GONZALEZ, H. VAUDRY, and S. JEGOU Expression of PACAP Receptor mRNAs by Neuropeptide Y Neurons in the Rat Arcuate Nucleus Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 457 - 461. [Abstract] [Full Text] [PDF]
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M. NAJIMI, F. RACHIDI, A. AFIF, and F. CHIGR Developmental Pattern of VIP Binding Sites in the Human Hypothalamus Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 462 - 467. [Abstract] [Full Text] [PDF]
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J. NEMETH, A. TAMAS, R. JOZSA, J. E. HORVATH, B. JAKAB, I. LENGVARI, A. ARIMURA, A. LUBICS, and D. REGLODI Changes in PACAP Levels in the Central Nervous System after Ovariectomy and Castration Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 468 - 473. [Abstract] [Full Text] [PDF]
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R. OKADA, K. YAMAMOTO, Y. ITO, N. CHARTREL, J. LEPRINCE, A. FOURNIER, H. VAUDRY, and S. KIKUYAMA Effects of Pituitary Adenylate Cyclase-Activating Polypeptide, Vasoactive Intestinal Polypeptide, and Somatostatin on the Release of Thyrotropin from the Bullfrog Pituitary Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 474 - 480. [Abstract] [Full Text] [PDF]
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T. SEKI, M. NAKATANI, C. TAKI, Y. SHINOHARA, M. OZAWA, S. NISHIMURA, H. ITO, and S. SHIODA Neuroprotective Effect of PACAP against Kainic Acid-Induced Neurotoxicity in Rat Retina Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 531 - 534. [Abstract] [Full Text] [PDF]
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T. SEKI, Y. HINOHARA, C. TAKI, M. NAKATANI, M. OZAWA, S. NISHIMURA, A. TAKAKI, H. ITHO, F. TAKENOYA, and S. SHIODA PACAP Stimulates the Release of Interleukin-6 in Cultured Rat Muller Cells Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 535 - 539. [Abstract] [Full Text] [PDF]
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N. SHINTANI, H. HASHIMOTO, K. TANAKA, N. KAWAGISHI, C. KAWAGUCHI, M. HATANAKA, Y. AGO, T. MATSUDA, and A. BABA Serotonergic Inhibition of Intense Jumping Behavior in Mice Lacking PACAP (Adcyap1-/-) Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 545 - 549. [Abstract] [Full Text] [PDF]
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P. SOKOLOWSKA and J. Z. NOWAK Cyclic AMP Formation in C6 Glioma Cells: Effect of PACAP and VIP in Early and Late Passages Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 566 - 569. [Abstract] [Full Text] [PDF]
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A. TAMAS, A. LUBICS, I. LENGVARI, and D. REGLODI Protective Effects of PACAP in Excitotoxic Striatal Lesion Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 570 - 574. [Abstract] [Full Text] [PDF]
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N. TOKUDA, Y. ARUDCHELVAN, T. SAWADA, Y. ADACHI, T. FUKUMOTO, M. YASUDA, H. SUMIDA, S. SHIODA, T. FUKUDA, A. ARIMA, et al. PACAP Receptor (PAC1-R) Expression in Rat and Rhesus Monkey Thymus Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 581 - 585. [Abstract] [Full Text] [PDF]
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M. USHIYAMA, H. SUGAWARA, K. INOUE, K. KANGAWA, K. YAMADA, and A. MIYATA Characterization of the PAC1 Variants Expressed in the Mouse Heart Ann. N.Y. Acad. Sci., July 1, 2006; 1070(1): 586 - 590. [Abstract] [Full Text] [PDF]
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