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Gene Review

GHRHR  -  growth hormone releasing hormone receptor

Homo sapiens

Synonyms: GHRFR, GHRH receptor, GRF receptor, GRFR, Growth hormone-releasing factor receptor, ...
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Disease relevance of GHRHR


High impact information on GHRHR

  • Since the identification of the GHRH peptide, recombinant DNA procedures have been used to characterize the corresponding cDNA and to clone GHRH receptor isoforms in rodent and human pituitaries [5].
  • The continuation of the deduced protein sequence coded by exons 4-13 in SV(1) is identical to that of pituitary GHRH-R [3].
  • BamHI RFLP for the GHRHR locus [6].
  • These findings were consistent with the results that the region from -310 to -130 is an important element for Pit-1-dependent expression of GHRH-R gene [7].
  • Deletion study showed that the regions from -310 to -130 and from -130 to -120 were important for the GHRH-R gene expression in GH3 cells, although the latter contributed less to the gene expression [7].

Biological context of GHRHR

  • These 3 families as well as 2 families in which linkage analysis was not performed were screened for mutations in the 13 coding exons, the intron-exon boundaries, and 327 bases of the promoter of the GHRHR gene [8].
  • In this chapter, we describe the GHRHR mutations reported to date and the phenotype of affected individuals [9].
  • We identified novel GHRHR missense mutations in 2 of the 3 kindreds with informative linkage and in 1 family in which linkage had not been performed [8].
  • More recently, kindreds in which IGHD subjects are compound heterozygotes for two distinct mutations indicate that faulty GHRHR alleles may be prevalent and that these mutations may need to be suspected even in sporadic IGHD cases [9].
  • The first human GHRHR mutations were discovered in families with a history of parental consanguinity [9].

Anatomical context of GHRHR

  • In order to determine whether the mutant receptor was properly expressed on the cell membrane surface, CHO cells were transfected with wild-type or mutant GHRHR cDNA containing a FLAG epitope tag in the extracellular N-terminus [10].
  • In contrast, GH-1, GHRH-R, and PROP-1 mutations were associated with consanguineous parents, intact pituitary stalk, normal posterior lobe, and pituitary origin of hormonal deficiencies [11].
  • GHRH is released by the hypothalamus into the portal hypophysial circulation to bind to a membrane surface receptor [GHRH receptor (GHRHR)] expressed by the somatotropic cells [9].
  • A splice variant (SV) of the full-length receptor for GHRH (GHRHR) is widely expressed in various primary human cancers and established cancer cell lines and appears to mediate the proliferative effects of GHRH [2].
  • GHRH-R promoter (1456 bp) directed high levels of luciferase expression in GH4 rat pituitary cells whereas no activity was detected in JEG3 chorion carcinoma cells or COS-7 monkey kidney cells [12].

Associations of GHRHR with chemical compounds

  • As expected, GHRH significantly decreased, whereas DEX increased, the levels of GHRHR mRNA [13].
  • We were unable to demonstrate significant effects on GRF-R expression with infusions of human GH (hGH) or insulin-like growth factor 1, which stimulate growth in dw rats, but dexamethasone treatment induced a significant, time-related increase in GRF-R mRNA levels [14].
  • High doses of GHRP-2 treatment decreased the levels of both GHRH-R and GHS-R mRNA [13].
  • GHRH-R immunostaining was also demonstrated in the ovary: oocytes, follicular cells, granulosa, thecal and corpus luteum cells [15].
  • Time- and temperature-dependent internalization of stimulated GHRH-R was blocked by phenyl arsine oxide (PAO) in both cell types [16].

Physical interactions of GHRHR


Regulatory relationships of GHRHR

  • More recently, it was found that GHRH can also activate mitogen-activated protein (MAP) kinase both in pituitary cells and in a cell line overexpressing the GHRH receptor [18].
  • Transcription of the GHRH receptor gene promoter is enhanced by Pit-1 and by glucocorticoids but is inhibited by oestrogen [19].

Other interactions of GHRHR


Analytical, diagnostic and therapeutic context of GHRHR


  1. Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene. Salvatori, R., Hayashida, C.Y., Aguiar-Oliveira, M.H., Phillips, J.A., Souza, A.H., Gondo, R.G., Toledo, S.P., Conceicão, M.M., Prince, M., Maheshwari, H.G., Baumann, G., Levine, M.A. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  2. Stimulation of proliferation of MCF-7 breast cancer cells by a transfected splice variant of growth hormone-releasing hormone receptor. Barabutis, N., Tsellou, E., Schally, A.V., Kouloheri, S., Kalofoutis, A., Kiaris, H. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  3. Isolation and sequencing of cDNAs for splice variants of growth hormone-releasing hormone receptors from human cancers. Rekasi, Z., Czompoly, T., Schally, A.V., Halmos, G. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  4. Identification of alternatively spliced messenger ribonucleic acid encoding truncated growth hormone-releasing hormone receptor in human pituitary adenomas. Hashimoto, K., Koga, M., Motomura, T., Kasayama, S., Kouhara, H., Ohnishi, T., Arita, N., Hayakawa, T., Sato, B., Kishimoto, T. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  5. Neuroendocrine control of growth hormone secretion. Müller, E.E., Locatelli, V., Cocchi, D. Physiol. Rev. (1999) [Pubmed]
  6. BamHI RFLP for the GHRHR locus. Cao, Y., Wagner, J.K., Eblé, A., Hindmarsh, P., Mullis, P.E. Hum. Mol. Genet. (1994) [Pubmed]
  7. Cloning and characterization of the 5'-flanking region of the human growth hormone-releasing hormone receptor gene. Iguchi, G., Okimura, Y., Takahashi, T., Mizuno, I., Fumoto, M., Takahashi, Y., Kaji, H., Abe, H., Chihara, K. J. Biol. Chem. (1999) [Pubmed]
  8. Three new mutations in the gene for the growth hormone (gh)-releasing hormone receptor in familial isolated gh deficiency type ib. Salvatori, R., Fan, X., Phillips, J.A., Espigares-Martin, R., Martin De Lara, I., Freeman, K.L., Plotnick, L., Al-Ashwal, A., Levine, M.A. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  9. Familial Growth Hormone Deficiency and Mutations in the GHRH Receptor Gene. Alba, M., Salvatori, R. Vitam. Horm. (2004) [Pubmed]
  10. A new missense mutation in the growth hormone-releasing hormone receptor gene in familial isolated GH deficiency. Carakushansky, M., Whatmore, A.J., Clayton, P.E., Shalet, S.M., Gleeson, H.K., Price, D.A., Levine, M.A., Salvatori, R. Eur. J. Endocrinol. (2003) [Pubmed]
  11. Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes. Osorio, M.G., Marui, S., Jorge, A.A., Latronico, A.C., Lo, L.S., Leite, C.C., Estefan, V., Mendonca, B.B., Arnhold, I.J. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  12. Structure and regulation of the human growth hormone-releasing hormone receptor gene. Petersenn, S., Rasch, A.C., Heyens, M., Schulte, H.M. Mol. Endocrinol. (1998) [Pubmed]
  13. Differential Regulation of GHRH-Receptor and GHS-Receptor Expression by Long-Term In Vitro Treatment of Ovine Pituitary Cells with GHRP-2 and GHRH. Roh, S.G., Doconto, M., Feng, D.D., Chen, C. Endocrine (2006) [Pubmed]
  14. Pituitary growth hormone-releasing factor receptor expression in normal and dwarf rats. Carmignac, D.F., Flavell, D.M., Robinson, I.C. Neuroendocrinology (1996) [Pubmed]
  15. Cellular distribution of growth hormone-releasing hormone receptor in human reproductive system and breast and prostate cancers. Gallego, R., Pintos, E., García-Caballero, T., Raghay, K., Boulanger, L., Beiras, A., Gaudreau, P., Morel, G. Histol. Histopathol. (2005) [Pubmed]
  16. Internalization and trafficking of the human and rat growth hormone-releasing hormone receptor. Veyrat-Durebex, C., Pomerleau, L., Langlois, D., Gaudreau, P. J. Cell. Physiol. (2005) [Pubmed]
  17. Absence of constitutively activating mutations in the GHRH receptor in GH-producing pituitary tumors. Lee, E.J., Kotlar, T.J., Ciric, I., Lee, M.K., Lim, S.K., Lee, H.C., Huh, K.B., Mayo, K.E., Jameson, J.L. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  18. Hormonal control of growth hormone secretion. Pombo, M., Pombo, C.M., Garcia, A., Caminos, E., Gualillo, O., Alvarez, C.V., Casanueva, F.F., Dieguez, C. Horm. Res. (2001) [Pubmed]
  19. Molecular and cell biology of the growth hormone-releasing hormone receptor. Gaylinn, B.D. Growth Horm. IGF Res. (1999) [Pubmed]
  20. Growth hormone-releasing hormone and growth hormone-releasing peptide as therapeutic agents to enhance growth hormone secretion in disease and aging. Thorner, M.O., Chapman, I.M., Gaylinn, B.D., Pezzoli, S.S., Hartman, M.L. Recent Prog. Horm. Res. (1997) [Pubmed]
  21. Inhibitory effects of antagonistic analogs of GHRH on GH3 pituitary cells overexpressing the human GHRH receptor. Kovacs, M., Schally, A.V., Lee, E.J., Busto, R., Armatis, P., Groot, K., Varga, J.L. J. Endocrinol. (2002) [Pubmed]
  22. Mapping the human growth hormone-releasing hormone receptor (GHRHR) gene to the short arm of chromosome 7 (7p13-p21) near the epidermal growth factor receptor (EGFR) gene. Vamvakopoulos, N.C., Kunz, J., Olberding, U., Scherer, S.W., Sioutopoulou, T.O., Schneider, V., Durkin, A.S., Nierman, W.C. Genomics (1994) [Pubmed]
  23. Pituitary mRNA expression of the growth hormone axis in the 1-year-old intrauterine growth restricted rat. Prins, T., Fodor, M., Delemarre-van de Waal, H.A. J. Neuroendocrinol. (2006) [Pubmed]
  24. Assignment of the human growth hormone-releasing hormone receptor gene (GHRHR) to 7p14 by in situ hybridization. Gaylinn, B.D., von Kap-Herr, C., Golden, W.L., Thorner, M.O. Genomics (1994) [Pubmed]
  25. Restoration of growth hormone-releasing hormone (GHRH) responsiveness in pituitary GH3 cells by adenovirus-directed expression of the human GHRH receptor. Lee, E.J., Duan, W.R., Kotlar, T., Jameson, J.L. Endocrinology (2001) [Pubmed]
  26. Isolated growth hormone (GH) deficiency due to compound heterozygosity for two new mutations in the GH-releasing hormone receptor gene. Salvatori, R., Fan, X., Phillips, J.A., Prince, M., Levine, M.A. Clin. Endocrinol. (Oxf) (2001) [Pubmed]
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