Genomes and Genes
pituitary hormone regulating hormone receptors
Summary: Cell surface receptors that bind the hypothalamic hormones regulating pituitary cell differentiation, proliferation, and hormone synthesis and release, including the pituitary-releasing and release-inhibiting hormones. The pituitary hormone-regulating hormones are also released by cells other than hypothalamic neurons, and their receptors also occur on non-pituitary cells, especially brain neurons, where their role is less well understood. Receptors for dopamine, which is a prolactin release-inhibiting hormone as well as a common neurotransmitter, are not included here.
- Salvatori R, Hayashida C, Aguiar Oliveira M, Phillips J, Souza A, Gondo R, et al. Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene. J Clin Endocrinol Metab. 1999;84:917-23 pubmed..We describe a novel mutation in the GHRHR gene as cause of dwarfism in the largest kindred with familial IGHD described to date. ..
- Kiaris H, Chatzistamou I, Schally A, Halmos G, Varga J, Koutselini H, et al. Ligand-dependent and -independent effects of splice variant 1 of growth hormone-releasing hormone receptor. Proc Natl Acad Sci U S A. 2003;100:9512-7 pubmed..These findings indicate that SV1 can operate in a ligand-independent as well as a ligand-dependent manner. The overexpression of this form of GHRH receptor may be associated with carcinogenesis. ..
- Wajnrajch M, Gertner J, Harbison M, Chua S, Leibel R. Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse. Nat Genet. 1996;12:88-90 pubmed
- Busto R, Schally A, Varga J, Garcia Fernandez M, Groot K, Armatis P, et al. The expression of growth hormone-releasing hormone (GHRH) and splice variants of its receptor in human gastroenteropancreatic carcinomas. Proc Natl Acad Sci U S A. 2002;99:11866-71 pubmed..The finding of SV(1) receptor in human cancers provides an approach to an antitumor therapy based on the blockade of this receptor by specific GHRH antagonists. ..
- Barabutis N, Tsellou E, Schally A, Kouloheri S, Kalofoutis A, Kiaris H. Stimulation of proliferation of MCF-7 breast cancer cells by a transfected splice variant of growth hormone-releasing hormone receptor. Proc Natl Acad Sci U S A. 2007;104:5575-9 pubmed..Collectively, our findings show that the expression of SV1 confers oncogenic activity and provide further evidence that GHRH operates as a growth factor in breast cancer and probably other cancers as well. ..
- Plonowski A, Schally A, Busto R, Krupa M, Varga J, Halmos G. Expression of growth hormone-releasing hormone (GHRH) and splice variants of GHRH receptors in human experimental prostate cancers. Peptides. 2002;23:1127-33 pubmed..The antiproliferative effects of GHRH antagonists on growth of prostate cancer could be exerted in part by an interference with this local GHRH system. ..
- Cardoso J, Power D, Elgar G, Clark M. Genomic characterisation of putative growth hormone releasing hormone (GHRH) receptor genes in the teleost fish Fugu rubripes. DNA Seq. 2003;14:129-33 pubmed..This is the first time that the genomic organisation of a GHRH receptor gene has been characterised from a nonmammalian vertebrate. ..
- Moretti C, Mencacci C, Frajese G, Cerilli M, Frajese G. Growth hormone-releasing hormone and pituitary adenylate cyclase-activating polypeptide in the reproductive system. Trends Endocrinol Metab. 2002;13:428-35 pubmed
- Kobayashi I, Oka H, Naritaka H, Sato Y, Fujii K, Kameya T. Expression of Pit-1 and growth hormone-releasing hormone receptor mRNA in human pituitary adenomas: difference among functioning, silent, and other nonfunctioning adenomas. Endocr Pathol. 2002;13:83-98 pubmed
- Stangelberger A, Schally A, Djavan B. New treatment approaches for prostate cancer based on peptide analogues. Eur Urol. 2008;53:890-900 pubmed publisher..New promising forms of hormone therapy and targeted chemotherapy may improve therapy of advanced stage prostate cancer. ..
- Roh S, Chen C, Choi K, Shrestha Y, Sasaki S. Is GHRH receptor essential to GHRP-2-induced GH secretion in primary cultured rat pituitary cells?. Endocrinology. 2002;143:1964-7 pubmed..These results suggest that GHRH-R is vital for GHRH-induced GH secretion but only partially involved in GHRP-2-stimulated GH secretion under the condition of down-regulation of GHS-R gene transcription. ..
- Garcia Tornadú I, Rubinstein M, Gaylinn B, Hill D, Arany E, Low M, et al. GH in the dwarf dopaminergic D2 receptor knockout mouse: somatotrope population, GH release, and responsiveness to GH-releasing factors and somatostatin. J Endocrinol. 2006;190:611-9 pubmed..Our data also reveal that somatotrope cell number is much more sensitive to changes in neonatal GHRH input than their capacity to develop properly regulated GH-secretory function. ..
- Park S, Peng X, Frohman L, Kineman R. Expression analysis of hypothalamic and pituitary components of the growth hormone axis in fasted and streptozotocin-treated neuropeptide Y (NPY)-intact (NPY+/+) and NPY-knockout (NPY-/-) mice. Neuroendocrinology. 2005;81:360-71 pubmed
- Roh S, Nie G, Loneragan K, Gertler A, Chen C. Direct modification of somatotrope function by long-term leptin treatment of primary cultured ovine pituitary cells. Endocrinology. 2001;142:5167-71 pubmed..It is also suggested that GHRP may be useful to correct the decrease in GHRH-induced GH secretion by leptin. ..
- Hashimoto K, Koga M, Motomura T, Kasayama S, Kouhara H, Ohnishi T, et al. Identification of alternatively spliced messenger ribonucleic acid encoding truncated growth hormone-releasing hormone receptor in human pituitary adenomas. J Clin Endocrinol Metab. 1995;80:2933-9 pubmed..These results suggest that some GH-producing adenomas preferentially express the truncated GHRH-R as a nonfunctioning receptor through alternative splicing. ..
- Siejka A, Schally A, Barabutis N. Activation of Janus kinase/signal transducer and activator of transcription 3 pathway by growth hormone-releasing hormone. Cell Mol Life Sci. 2010;67:959-64 pubmed publisher..Our work demonstrates the activation of JAK/STAT3 pathway by GHRH and sheds further light to the mechanisms of the antitumorogenic action of GHRH antagonists. ..
- Wester T, Fiorotto M, Klindt J, Burrin D. Feeding colostrum increases circulating insulin-like growth factor I in newborn pigs independent of endogenous growth hormone secretion. J Anim Sci. 1998;76:3003-9 pubmed
- Granata R, Trovato L, Gallo M, Destefanis S, Settanni F, Scarlatti F, et al. Growth hormone-releasing hormone promotes survival of cardiac myocytes in vitro and protects against ischaemia-reperfusion injury in rat heart. Cardiovasc Res. 2009;83:303-12 pubmed publisher..Our findings suggest that GHRH promotes cardiac myocyte survival through multiple signalling mechanisms and protects against I/R injury in isolated rat heart, indicating a novel cardioprotective role of this hormone. ..
- Gaylinn B, DeAlmeida V, Lyons C, Wu K, Mayo K, Thorner M. The mutant growth hormone-releasing hormone (GHRH) receptor of the little mouse does not bind GHRH. Endocrinology. 1999;140:5066-74 pubmed
- Gondo R, Aguiar Oliveira M, Hayashida C, Toledo S, Abelin N, Levine M, et al. Growth hormone-releasing peptide-2 stimulates GH secretion in GH-deficient patients with mutated GH-releasing hormone receptor. J Clin Endocrinol Metab. 2001;86:3279-83 pubmed..These results suggest that an intact GHRH signaling system is not an absolute requirement for GHRP-2 action on GH secretion and that GHRP-2 has a GHRH-independent effect on pituitary somatotroph cells. ..
- Espigares R, Martin De Lara I, Ruiz Cabello F, Ortega L, Ferrandez Longas A, Argente J, et al. Phenotypic analysis and growth response to different growth hormone treatment schedules in two siblings with an inactivating mutation in the growth hormone-releasing hormone receptor gene. J Pediatr Endocrinol Metab. 2004;17:793-800 pubmed
- Oliveira C, Salvatori R, Meneguz Moreno R, Aguiar Oliveira M, Pereira R, Valença E, et al. Adipokine profile and urinary albumin excretion in isolated growth hormone deficiency. J Clin Endocrinol Metab. 2010;95:693-8 pubmed publisher..7 ng/ml] and UAE [8.6 (13.8) vs. 8.5 (11.1) microg/min]. Subjects with lifetime untreated IGHD have an adipokine profile with high adiponectin and normal leptin levels that may delay vascular damage and lesions of the renal endothelium. ..
- Morishita M, Iwasaki Y, Onishi A, Asai M, Mutsuga N, Yoshida M, et al. The effects of GH-releasing hormone/somatostatin on the 5'-promoter activity of the GH gene in vitro. J Mol Endocrinol. 2003;31:441-8 pubmed..The MtT/SGL cell line is a good in vitro model for studying the molecular mechanisms of GH gene transcription by GHRH and/or SRIF. ..
- Baumann G. Mutations in the growth hormone releasing hormone receptor: a new form of dwarfism in humans. Growth Horm IGF Res. 1999;9 Suppl B:24-9; discussion 29-30 pubmed..Bone age and puberty are delayed, but fertility appears normal. This new syndrome corresponds to the human homologue of the previously identified 'little mouse'. ..
- Kovacs M, Kineman R, Schally A, Flerko B, Frohman L. Increase in mRNA concentrations of pituitary receptors for growth hormone-releasing hormone and growth hormone secretagogues after neonatal monosodium glutamate treatment. J Neuroendocrinol. 2000;12:335-41 pubmed..Collectively, our observations demonstrate a complex interplay between transcriptional, translational and post-translational mechanisms within each level of the GH-axis following destruction of GHRH neurones by neonatal MSG treatment. ..
- Obal F, Alt J, Taishi P, Gardi J, Krueger J. Sleep in mice with nonfunctional growth hormone-releasing hormone receptors. Am J Physiol Regul Integr Comp Physiol. 2003;284:R131-9 pubmed..The results suggest that GH promotes REMS whereas GHRH stimulates NREMS via central GHRH-Rs and that GHRH is involved in the mediation of the sleep effects of ghrelin and somatostatin. ..
- Shimokawa I, Yanagihara K, Higami Y, Okimoto T, Tomita M, Ikeda T, et al. Effects of aging and dietary restriction on mRNA levels of receptors for growth hormone-releasing hormone and somatostatin in the rat pituitary. J Gerontol A Biol Sci Med Sci. 2000;55:B274-9 pubmed..Although DR could slightly enhance the pituitary sensitivity to GHRH, the antiaging action may be minor at the level of gene expression. ..
- de Paula F, Gois Junior M, Aguiar Oliveira M, Pereira F, Oliveira C, Pereira R, et al. Consequences of lifetime isolated growth hormone (GH) deficiency and effects of short-term GH treatment on bone in adults with a mutation in the GHRH-receptor gene. Clin Endocrinol (Oxf). 2009;70:35-40 pubmed publisher..The treatment induces a biochemical pattern of bone anabolism that persists for at least 6 months after treatment discontinuation. ..
- Smith R, Palyha O, Feighner S, Tan C, McKee K, Hreniuk D, et al. Growth hormone releasing substances: types and their receptors. Horm Res. 1999;51 Suppl 3:1-8 pubmed..This new information is consistent with a natural ligand for the GHS-R playing a fundamentally important and conserved role in physiology. ..
- Salvatori R, Fan X, Phillips J, Prince M, Levine M. Isolated growth hormone (GH) deficiency due to compound heterozygosity for two new mutations in the GH-releasing hormone receptor gene. Clin Endocrinol (Oxf). 2001;54:681-7 pubmed..We describe a family in which two siblings with IGHD were compound heterozygotes for two new mutations in the GHRH-R gene. These results suggest that mutant alleles for GHRH-R gene may be more common than previously suspected. ..
- van Heemst D, Beekman M, Mooijaart S, Heijmans B, Brandt B, Zwaan B, et al. Reduced insulin/IGF-1 signalling and human longevity. Aging Cell. 2005;4:79-85 pubmed..This effect was stronger for the GH1 SNP than for variation in the conserved IIS genes that were found to affect longevity in model organisms. ..
- Wajnrajch M, Gertner J, Sokoloff A, Ten I, Harbison M, Netchine I, et al. Haplotype analysis of the growth hormone releasing hormone receptor locus in three apparently unrelated kindreds from the indian subcontinent with the identical mutation in the GHRH receptor. Am J Med Genet A. 2003;120A:77-83 pubmed..5 centimorgan (cM) region around GHRHR on chromosome 7p15. We conclude that the affected individuals share a common ancestor, and we use the association with linked markers to estimate the age of this unique mutation. ..
- Luque R, Kineman R, Park S, Peng X, Gracia Navarro F, Castaño J, et al. Homologous and heterologous regulation of pituitary receptors for ghrelin and growth hormone-releasing hormone. Endocrinology. 2004;145:3182-9 pubmed..However, our results also indicate that the expression of porcine GHRH-R and GHS-R is regulated by distinct signals that may differ from those reported in other mammalian species. ..
- Park S, Sohn S, Kineman R. Fasting-induced changes in the hypothalamic-pituitary-GH axis in the absence of GH expression: lessons from the spontaneous dwarf rat. J Endocrinol. 2004;180:369-78 pubmed
- Lumpkin M, McDonald J. Blockade of growth hormone-releasing factor (GRF) activity in the pituitary and hypothalamus of the conscious rat with a peptidic GRF antagonist. Endocrinology. 1989;124:1522-31 pubmed
- Bodart V, Febbraio M, Demers A, McNicoll N, Pohankova P, Perreault A, et al. CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Circ Res. 2002;90:844-9 pubmed..These data suggest that CD36 may mediate the coronary vasospasm seen in hypercholesterolemia and atherosclerosis. ..
- Alba M, Salvatori R. Naturally-occurring missense mutations in the human growth hormone-releasing hormone receptor alter ligand binding. J Endocrinol. 2005;186:515-21 pubmed..These studies demonstrate that abnormal ligand binding is a common mechanism by which naturally occurring missense mutation alter GHRH-R function. ..
- Taishi P, De A, Alt J, Gardi J, Obal F, Krueger J. Interleukin-1beta stimulates growth hormone-releasing hormone receptor mRNA expression in the rat hypothalamus in vitro and in vivo. J Neuroendocrinol. 2004;16:113-8 pubmed..IL-1beta also elicited slight GHRH releases in vitro. Up-regulation of hypothalamic GHRH-R by IL-1beta may explain previous findings suggesting that IL-1beta stimulates GHRH activity. ..
- Kineman R, Luque R. Evidence that ghrelin is as potent as growth hormone (GH)-releasing hormone (GHRH) in releasing GH from primary pituitary cell cultures of a nonhuman primate (Papio anubis), acting through intracellular signaling pathways distinct from GHRH. Endocrinology. 2007;148:4440-9 pubmed publisher..Together, these results present the first evidence that a direct effect of ghrelin on somatotrope function may play a major role in stimulating GH release in primates...
- Rodriguez Pacheco F, Vazquez Martinez R, Martinez Fuentes A, Pulido M, Gahete M, Vaudry H, et al. Resistin regulates pituitary somatotrope cell function through the activation of multiple signaling pathways. Endocrinology. 2009;150:4643-52 pubmed publisher..Taken together, our results demonstrate for the first time a regulatory role for resistin on somatotrope function and provide novel insights on the intracellular mechanisms activated by this protein. ..
- Chatzistamou I, Volakaki A, Schally A, Kiaris H, Kittas C. Expression of growth hormone-releasing hormone receptor splice variant 1 in primary human melanomas. Regul Pept. 2008;147:33-6 pubmed publisher..Our findings also suggest that treatment with GHRH antagonists should be further explored for the management of malignant melanomas. ..
- Desai M, Upadhye P, Kamijo T, Yamamoto M, Ogawa M, Hayashi Y, et al. Growth hormone releasing hormone receptor (GHRH-r) gene mutation in Indian children with familial isolated growth hormone deficiency: a study from western India. J Pediatr Endocrinol Metab. 2005;18:955-73 pubmed..GHRH-R gene mutations may be the most reasonable candidate for IGHD-IB with the E72X mutation predominating in the Indian subcontinent. More extensive studies need to be undertaken. ..
- Mayo K, Miller T, DeAlmeida V, Zheng J, Godfrey P. The growth-hormone-releasing hormone receptor: signal transduction, gene expression, and physiological function in growth regulation. Ann N Y Acad Sci. 1996;805:184-203 pubmed..Finally, a major direction we are taking in the laboratory at the present time is toward understanding the developmental, hormonal, and tissue-specific regulation of the GHRH receptor gene. ..
- Morel G, Gallego R, Boulanger L, Pintos E, Garcia Caballero T, Gaudreau P. Restricted presence of the growth hormone-releasing hormone receptor to somatotropes in rat and human pituitaries. Neuroendocrinology. 1999;70:128-36 pubmed
- Carakushansky M, Whatmore A, Clayton P, Shalet S, Gleeson H, Price D, et al. A new missense mutation in the growth hormone-releasing hormone receptor gene in familial isolated GH deficiency. Eur J Endocrinol. 2003;148:25-30 pubmed..We describe two siblings with IGHD due to a new mutation in the GHRHR that disrupts GHRH signaling and leads to GHRH resistance. ..
- Nogami H, Matsubara M, Harigaya T, Katayama M, Kawamura K. Retinoic acids and thyroid hormone act synergistically with dexamethasone to increase growth hormone-releasing hormone receptor messenger ribonucleic acid expression. Endocrinology. 2000;141:4396-401 pubmed
- Lasko C, Korytko A, Wehrenberg W, Cuttler L. Differential GH-releasing hormone regulation of GHRH receptor mRNA expression in the rat pituitary. Am J Physiol Endocrinol Metab. 2001;280:E626-31 pubmed
- Kageyama K, Kushibiki M, Hanada K, Sakihara S, Yasujima M, Suda T. Growth hormone-releasing peptide-2 stimulates secretion and synthesis of adrenocorticotropic hormone in mouse pituitary. Regul Pept. 2009;158:116-20 pubmed publisher..Together, the GHRP-2-induced ACTH release was regulated via both PKA and PKC pathways in the mouse pituitary cells, while ACTH was synthesized by GHRP-2 only via the PKA pathway. ..
- Wang Q, Diao Y, Xu Z, Li X, Luo X, Xu H, et al. Identification of a novel splicing mutation in the growth hormone (GH)-releasing hormone receptor gene in a Chinese family with pituitary dwarfism. Mol Cell Endocrinol. 2009;313:50-6 pubmed publisher..These results provide strong evidence that the splicing mutation IVS8+1G>A of GHRHR is a cause of pituitary dwarfism in the Chinese family...
- Aguiar Oliveira M, Oliveira F, Pereira R, Oliveira C, Blackford A, Valenca E, et al. Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the GHRH receptor gene. J Clin Endocrinol Metab. 2010;95:714-21 pubmed publisher..The prevalence of heterozygosity did not differ in young and old groups, suggesting no survival advantage or disadvantage. In a selected genetic background, lifelong untreated IGHD does not affect longevity. ..
- Alba M, Hall C, Whatmore A, Clayton P, Price D, Salvatori R. Variability in anterior pituitary size within members of a family with GH deficiency due to a new splice mutation in the GHRH receptor gene. Clin Endocrinol (Oxf). 2004;60:470-5 pubmed
- Jansson J, Downs T, Beamer W, Frohman L. Receptor-associated resistance to growth hormone-releasing factor in dwarf "little" mice. Science. 1986;232:511-2 pubmed..The basis of the GH deficiency in the little mouse may therefore be a defect in an early stage of GRF-stimulated GH release related either to receptor binding or to the function of the hormone-receptor complex. ..