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Science 16 August 1996:
Vol. 273. no. 5277, pp. 974 - 977
DOI: 10.1126/science.273.5277.974
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Reports

A Receptor in Pituitary and Hypothalamus That Functions in Growth Hormone Release

Andrew D. Howard, * Scott D. Feighner, * Doris F. Cully, Joseph P. Arena, Paul A. Liberator, Charles I. Rosenblum, Michel Hamelin, Donna L. Hreniuk, Oksana C. Palyha, Jennifer Anderson, Philip S. Paress, Carmen Diaz, Michael Chou, Ken K. Liu, Karen Kulju McKee, Sheng-Shung Pong, Lee-Yuh Chaung, Alex Elbrecht, Mike Dashkevicz, Robert Heavens, Mike Rigby, Dalip J. S. Sirinathsinghji, Dennis C. Dean, David G. Melillo, Arthur A. Patchett, Ravi Nargund, Patrick R. Griffin, Julie A. DeMartino, Sunil K. Gupta, James M. Schaeffer, Roy G. Smith, Lex H. T. Van der Ploeg dagger

Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.

A. D. Howard, S. D. Feighner, D. F. Cully, J. P. Arena, P. A. Liberator, C. I. Rosenblum, M. Hamelin, D. L. Hreniuk, O. C. Palyha, J. Anderson, P. S. Paress, C. Diaz, M. Chou, K. K. Liu, K. K. McKee, S.-S. Pong, L.-Y. Chaung, A. Elbrecht, M. Dashkevicz, D. C. Dean, D. G. Melillo, A. A. Patchett, R. Nargund, P. R. Griffin, J. A. DeMartino, S. K. Gupta, J. M. Schaeffer, R. G. Smith, L. H. T. Van der Ploeg, Merck Research Laboratories, Rahway, NJ 07065, USA.
R. Heavens, M. Rigby, D. J. S. Sirinathsinghji, Merck Sharp & Dohme, Neuroscience Research Center Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed.


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Ghrelin and Growth Hormone Secretagogue Receptor Expression in Mice during Aging.
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Regulation of Pituitary Cell Function by Adiponectin.
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Endocrinology 148, 401-410
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Endocrinology 147, 4093-4103
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Characterization of ghrelin receptor activity in a rat pituitary cell line RC-4B/C..
H D. Falls, B. D Dayton, D. G Fry, C. A Ogiela, V. G Schaefer, S. Brodjian, R. M Reilly, C. A Collins, and W. Kaszubska (2006)
J. Mol. Endocrinol. 37, 51-62
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Ghrelin Amplifies Dopamine Signaling by Cross Talk Involving Formation of Growth Hormone Secretagogue Receptor/Dopamine Receptor Subtype 1 Heterodimers.
H. Jiang, L. Betancourt, and R. G. Smith (2006)
Mol. Endocrinol. 20, 1772-1785
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Role of Endogenous Ghrelin in the Hyperphagia of Mice with Streptozotocin-Induced Diabetes.
J. Dong, T. L. Peeters, B. De Smet, D. Moechars, C. Delporte, P. Vanden Berghe, B. Coulie, M. Tang, and I. Depoortere (2006)
Endocrinology 147, 2634-2642
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Ghrelin receptors in rat and human nodose ganglia: putative role in regulating CB-1 and MCH receptor abundance.
G. Burdyga, A. Varro, R. Dimaline, D. G. Thompson, and G. J. Dockray (2006)
Am J Physiol Gastrointest Liver Physiol 290, G1289-G1297
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Differential Contributions of Motilin Receptor Extracellular Domains for Peptide and Non-peptidyl Agonist Binding and Activity.
B. Matsuura, M. Dong, S. Naik, L. J. Miller, and M. Onji (2006)
J. Biol. Chem. 281, 12390-12396
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Comparative Analysis of the Effects of Ghrelin and Unacylated Ghrelin on Luteinizing Hormone Secretion in Male Rats.
A. C. Martini, R. Fernandez-Fernandez, S. Tovar, V. M. Navarro, E. Vigo, M. J. Vazquez, J. S. Davies, N. M. Thompson, E. Aguilar, L. Pinilla, et al. (2006)
Endocrinology 147, 2374-2382
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Des-Acyl Ghrelin Induces Food Intake by a Mechanism Independent of the Growth Hormone Secretagogue Receptor.
K. Toshinai, H. Yamaguchi, Y. Sun, R. G. Smith, A. Yamanaka, T. Sakurai, Y. Date, M. S. Mondal, T. Shimbara, T. Kawagoe, et al. (2006)
Endocrinology 147, 2306-2314
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The Physiology and Potential Clinical Applications of Ghrelin, a Novel Peptide Hormone.
N. A. Tritos and E. G. Kokkotou (2006)
Mayo Clin. Proc. 81, 653-660
   Abstract »    Full Text »    PDF »
Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition.
J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, and C. Y. Bowers (2006)
Endocr. Rev. 27, 101-140
   Abstract »    Full Text »    PDF »
Ghrelin Neutralization by a Ribonucleic Acid-SPM Ameliorates Obesity in Diet-Induced Obese Mice.
L. P. Shearman, S.-P. Wang, S. Helmling, D. S. Stribling, P. Mazur, L. Ge, L. Wang, S. Klussmann, D. E. Macintyre, A. D. Howard, et al. (2006)
Endocrinology 147, 1517-1526
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IA-2beta, but not IA-2, is induced by ghrelin and inhibits glucose-stimulated insulin secretion.
A. Doi, T. Shono, M. Nishi, H. Furuta, H. Sasaki, and K. Nanjo (2006)
PNAS 103, 885-890
   Abstract »    Full Text »    PDF »
Ghrelin and unacylated ghrelin stimulate human osteoblast growth via mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K) pathways in the absence of GHS-R1a.
P J D Delhanty, B C J van der Eerden, M van der Velde, C Gauna, H A P Pols, H Jahr, H Chiba, A J van der Lely, and J P T M van Leeuwen (2006)
J. Endocrinol. 188, 37-47
   Abstract »    Full Text »    PDF »
Energy Homeostasis and Gastric Emptying in Ghrelin Knockout Mice.
B. De Smet, I. Depoortere, D. Moechars, Q. Swennen, B. Moreaux, K. Cryns, J. Tack, J. Buyse, B. Coulie, and T. L. Peeters (2006)
J. Pharmacol. Exp. Ther. 316, 431-439
   Abstract »    Full Text »    PDF »
Expression and function of the ghrelin axis, including a novel preproghrelin isoform, in human breast cancer tissues and cell lines.
P L Jeffery, R E Murray, A H Yeh, J F McNamara, R P Duncan, G D Francis, A C Herington, and L K Chopin (2005)
Endocr. Relat. Cancer 12, 839-850
   Abstract »    Full Text »    PDF »
International Union of Pharmacology. LVI. Ghrelin Receptor Nomenclature, Distribution, and Function.
A. P. Davenport, T. I. Bonner, S. M. Foord, A. J. Harmar, R. R. Neubig, J.-P. Pin, M. Spedding, M. Kojima, and K. Kangawa (2005)
Pharmacol. Rev. 57, 541-546
   Abstract »    Full Text »    PDF »
Obestatin, a Peptide Encoded by the Ghrelin Gene, Opposes Ghrelin's Effects on Food Intake.
J. V. Zhang, P.-G. Ren, O. Avsian-Kretchmer, C.-W. Luo, R. Rauch, C. Klein, and A. J. W. Hsueh (2005)
Science 310, 996-999
   Abstract »    Full Text »    PDF »
The Intermediate Lactotroph: A Morphologically Distinct, Ghrelin-Responsive Pituitary Cell in the Dwarf (dw/dw) Rat.
I. Huerta-Ocampo, H. C. Christian, N. M. Thompson, M. M. El-Kasti, and T. Wells (2005)
Endocrinology 146, 5012-5023
   Abstract »    Full Text »    PDF »
Effects of long-term treatment with growth hormone-releasing peptide-2 in the GHRH knockout mouse.
M. Alba, D. Fintini, C. Y. Bowers, A. F. Parlow, and R. Salvatori (2005)
Am J Physiol Endocrinol Metab 289, E762-E767
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GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failure.
X.-B. Xu, J.-J. Pang, J.-M. Cao, C. Ni, R.-K. Xu, X.-Z. Peng, X.-X. Yu, S. Guo, M.-C. Chen, and C. Chen (2005)
Am J Physiol Heart Circ Physiol 289, H1643-H1651
   Abstract »    Full Text »    PDF »
Nonpeptide and Peptide Growth Hormone Secretagogues Act Both as Ghrelin Receptor Agonist and as Positive or Negative Allosteric Modulators of Ghrelin Signaling.
B. Holst, E. Brandt, A. Bach, A. Heding, and T. W. Schwartz (2005)
Mol. Endocrinol. 19, 2400-2411
   Abstract »    Full Text »    PDF »
Endogenous Ghrelin Regulates Episodic Growth Hormone (GH) Secretion by Amplifying GH Pulse Amplitude: Evidence from Antagonism of the GH Secretagogue-R1a Receptor.
P. Zizzari, H. Halem, J. Taylor, J. Z. Dong, R. Datta, M. D. Culler, J. Epelbaum, and M. T. Bluet-Pajot (2005)
Endocrinology 146, 3836-3842
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Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro.
T Kitazawa, B De Smet, K Verbeke, I Depoortere, and T L Peeters (2005)
Gut 54, 1078-1084
   Abstract »    Full Text »    PDF »
Comparative study of plasma ghrelin levels in women with polycystic ovary syndrome, in hyperandrogenic women and in normal controls.
D. Panidis, D. Farmakiotis, G. Koliakos, D. Rousso, A. Kourtis, I. Katsikis, C. Asteriadis, V. Karayannis, and E. Diamanti-Kandarakis (2005)
Hum. Reprod. 20, 2127-2132
   Abstract »    Full Text »    PDF »
Ghrelin is an orexigenic and metabolic signaling peptide in the arcuate and paraventricular nuclei.
P. J. Currie, A. Mirza, R. Fuld, D. Park, and J. R. Vasselli (2005)
Am J Physiol Regulatory Integrative Comp Physiol 289, R353-R358
   Abstract »    Full Text »    PDF »
Enhanced ghrelin secretion in rats with cysteamine-induced duodenal ulcers.
S. Fukuhara, H. Suzuki, T. Masaoka, M. Arakawa, H. Hosoda, Y. Minegishi, K. Kangawa, H. Ishii, M. Kitajima, and T. Hibi (2005)
Am J Physiol Gastrointest Liver Physiol 289, G138-G145
   Abstract »    Full Text »    PDF »
Demonstration of a Specific Site of Covalent Labeling of the Human Motilin Receptor Using a Biologically Active Photolabile Motilin Analog.
B. Matsuura, M. Dong, B. Coulie, D. I. Pinon, and L. J. Miller (2005)
J. Pharmacol. Exp. Ther. 313, 1101-1108
   Abstract »    Full Text »    PDF »
Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion.
L. S. Farhy and J. D. Veldhuis (2005)
Am J Physiol Regulatory Integrative Comp Physiol 288, R1649-R1663
   Abstract »    Full Text »    PDF »
Development of Growth Hormone Secretagogues.
R. G. Smith (2005)
Endocr. Rev. 26, 346-360
   Abstract »    Full Text »    PDF »
Endogenous Circulating Ghrelin Does Not Mediate Growth Hormone Rhythmicity or Response to Fasting.
A. M. Avram, C. A. Jaffe, K. V. Symons, and A. L. Barkan (2005)
J. Clin. Endocrinol. Metab. 90, 2982-2987
   Abstract »    Full Text »    PDF »
Obesity and the Neuroendocrine Control of Energy Homeostasis: The Role of Spontaneous Locomotor Activity.
T. R. Castaneda, H. Jurgens, P. Wiedmer, P. Pfluger, S. Diano, T. L. Horvath, M. Tang-Christensen, and M. H. Tschop (2005)
J. Nutr. 135, 1314-1319
   Abstract »    Full Text »    PDF »
Ghrelin: Structure and Function.
M. Kojima and K. Kangawa (2005)
Physiol Rev 85, 495-522
   Abstract »    Full Text »    PDF »
Molecular Endocrinology and Physiology of the Aging Central Nervous System.
R. G. Smith, L. Betancourt, and Y. Sun (2005)
Endocr. Rev. 26, 203-250
   Abstract »    Full Text »    PDF »
Low Plasma Ghrelin Level in Gastrectomized Patients Is Accompanied by Enhanced Sensitivity to the Ghrelin-Induced Growth Hormone Release.
V. Popovic, D. Miljic, S. Pekic, P. Pesko, M. Djurovic, M. Doknic, S. Damjanovic, D. Micic, G. Cvijovic, J. Glodic, et al. (2005)
J. Clin. Endocrinol. Metab. 90, 2187-2191
   Abstract »    Full Text »    PDF »
Loss of Gq/11 Family G Proteins in the Nervous System Causes Pituitary Somatotroph Hypoplasia and Dwarfism in Mice.
N. Wettschureck, A. Moers, B. Wallenwein, A. F. Parlow, C. Maser-Gluth, and S. Offermanns (2005)
Mol. Cell. Biol. 25, 1942-1948
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Expression of Growth Hormone Secretagogue Receptor Type 1a, the Functional Ghrelin Receptor, in Human Ovarian Surface Epithelium, Mullerian Duct Derivatives, and Ovarian Tumors.
F. Gaytan, C. Morales, M. L. Barreiro, P. Jeffery, L. K. Chopin, A. C. Herington, F. F. Casanueva, E. Aguilar, C. Dieguez, and M. Tena-Sempere (2005)
J. Clin. Endocrinol. Metab. 90, 1798-1804
   Abstract »    Full Text »    PDF »
Ghrelin Is Produced by the Human Erythroleukemic HEL Cell Line and Involved in an Autocrine Pathway Leading to Cell Proliferation.
C. De Vriese, F. Gregoire, P. De Neef, P. Robberecht, and C. Delporte (2005)
Endocrinology 146, 1514-1522
   Abstract »    Full Text »    PDF »


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