High plasma growth hormone (GH) levels inhibit expression of GH secretagogue receptor messenger ribonucleic acid levels in the rat pituitary (original) (raw)
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Endocrinology, 2000
Synthetic GH secretagogues (GHSs) act via a receptor (GHS-R) distinct from that of GH-releasing hormone. The GHS-R has been cloned from the pituitary and is expressed not only in the pituitary but also in specific areas of the brain, including the hypothalamus. Recent studies suggest that hypothalamic GHS-R expression is regulated by GH. This study was designed to investigate whether pituitary GHS-R expression is modulated by GH. Female Wistar-Furth rats were injected sc with either saline (control) or GC tumor cells (GC) that secrete rat GH. The tumors were allowed to develop for 1-4 weeks. At weeks 1-4, control (n ϭ 4 -8) and GC rats (n ϭ 3-8) were killed. Pituitary GHS-R messenger RNA (mRNA) was measured by a quan-titative competitive PCR assay. The endogenous GHS-R mRNA levels were measured by determining the amount of competitive template RNA required to produce equimolar amounts of native and competitive template PCR products. The mean log plasma GH levels were significantly greater in the GC rat group than in the control group at weeks 2, 3, and 4. At these times, the mean log pituitary GHS-R mRNA contents were significantly lower in the GC rat group than in the control group. No relationship could be established between log estradiol levels and GHS-R levels. These data indicate that pituitary GHS-R expression is modulated by GH.
Both Estrogen Receptor α and β Stimulate Pituitary GH Gene Expression
Molecular Endocrinology, 2014
Although sex steroids have been implicated in the control of mammalian growth, their direct effect on GH synthesis is less clear. The aim of this study was to establish whether estradiol (E2) directly affects GH synthesis in somatotrophs. Somatotroph GH3 and MtT/S cells were used as in vitro models. At physiological doses of E2 stimulation, GH mRNA levels were increased and the ER antagonist ICI 182,780 completely abolished this effect. Estrogen receptor (ER) α– and ERβ-selective agonists, propylpyrazole triol (PPT), and 2,3-bis(4-hydroxyphenyl) propionitrile (DPN), respectively, augmented GH mRNA expression and secretion, whereas E2 and PPT, but not DPN increased prolactin (PRL) mRNA levels. E2, PPT, and DPN stimulated expression of the pituitary transcription factor Pou1f1 and increased its binding to the GH promoter. In vivo evidence of E2 effects on GH synthesis was obtained from the generation of the somatotroph-specific ERα knockout (sERα-KO) mouse model. Basal pituitary GH, P...
Endocrinology, 1997
Synthetic GH secretagogues (GHSs) act via a receptor (GHS-R) distinct from that for GH-releasing hormone (GHRH). We have studied the hypothalamic expression and regulation of this receptor by in situ hybridization using a homologous riboprobe for rat GHS-R. GHS-R mRNA is prominently expressed in arcuate (ARC) and ventromedial nuclei (VMN) and in hippocampus, but not in the periventricular nucleus. Little or no specific hybridization could be observed in the pituitary under the conditions that gave strong signals in the hypothalamus. No sex difference in GHS-R expression was found in ARC or hippocampus, though expression in VMN was lower in males than in females. Compared with GHRH and neuropeptide Y (NPY), GHS-R was expressed in a distinct region of ventral ARC, and in regions of VMN not expressing GHRH or NPY. GHS-R expression was highly sensitive to GH, being markedly increased in GH-deficient dw/dw dwarf rats, and decreased in dw/dw rats treated with bovine GH (200 g/day) for 6 days. Similar changes were observed in GHRH expression, whereas NPY expression was reduced in dw/dw rats and increased by bGH treatment. Continuous sc infusion of GHRP-6 in normal female rats did not alter ARC or VMN GHS-R expression. Our data implicate ARC and VMN cells as major hypothalamic targets for direct GHS action. The sensitivity of ARC GHS-R expression to modulation by GH suggests that GHS-Rs may be involved in feedback regulation of GH.
Alterations in GHRH binding and GHRH receptor mRNA in the pituitary of adult dw/dw rats
Peptides, 2002
Lewis dwarf (dw/dw) rats exhibit growth hormone (GH) deficiency and growth retardation linked to a malfunction of GHRH signaling. In this study, GHRH-receptor (GHRH-R) binding and mRNA in the pituitary of adult male dw/dw and age-matched normal Lewis rats was measured by radioligand binding assay and real-time PCR. Only one of nine pools of dw/dw pituitary membranes revealed detectable binding of [His 1 , 125 I-Tyr 10 , Nle 27 ]hGHRH(1-32) amide (B max ; 4.3 fmol/mg protein). In contrast, GHRH-R binding was 22.4 ± 2.60 fmol/mg protein in normal Lewis rats. mRNA for GHRH-R was detectable in all dw/dw rat pituitaries examined, averaging 21% that of Lewis rats. Low expression of GHRH-R reflects reduced GHRH-R mRNA as well as a possible reduction in translation of the receptor protein.
Molecular Analysis of Rat Pituitary and Hypothalamic Growth Hormone Secretagogue Receptors
Molecular Endocrinology, 1997
GH release is thought to occur under the reciprocal regulation of two hypothalamic peptides, GH releasing hormone (GHRH) and somatostatin, via their engagement with specific cell surface receptors on the anterior pituitary somatotroph. In addition, GH-releasing peptides, such as GHRP-6 and the nonpeptide mimetics, L-692,429 and MK-0677, stimulate GH release through their activation of a distinct receptor, the GH secretagogue receptor (GHS-R). The recent cloning of the GHS-R from human and swine pituitary gland identifies yet a third G protein-coupled receptor (GPC-R) involved in the control of GH release and further supports the existence of an undiscovered hormone that may activate this receptor. Using the human GHS-R as a probe, we report the isolation of a rat pituitary GHS-R cDNA derived from an unspliced, precursor mRNA. The rat cDNA encodes a protein of 364 amino acids containing seven transmembrane domains (7-TM) with >90% sequence identity to both the human and swine GHS-Rs. A single intron of ϳ2 kb divides the open reading frame into two exons encoding TM 1-5 and TM 6-7, thus placing the GHS-R into the intron-containing class of GPC-Rs. The intron maps to the site of sequence divergence between the human and swine type 1a and 1b GHS-R mRNAs. In addition, determination of the nucleotide sequence for the human GHS-R gene confirmed the position of an intron in the human GHS-R gene at this position. A full-length contiguous cDNA from rat hypothalamus was isolated and shown to be identical in its nucleotide and deduced amino acid sequence to the rat pituitary GHS-R. The cloned rat GHS-R binds [ 35 S]MK-0677 with high affinity [dissociation constant (K D) ؍ 0.7 nM] and is functionally active when expressed in HEK-293 cells. Expression of the rat GHS-R was observed specifically in the pituitary and hypothalamus when compared with control tissues. (Molecular Endocrinology 11: 415-423, 1997)
Growth hormone-releasing hormone: Extrapituitary effects in physiology and pathology
Cell Cycle, 2010
The existence of growth hormone-releasing hormone (GHRH) was first suggested in 1961, 1 but the breakthrough for the identification of this hormone was provided by the demonstration of the ectopic production of GHRH by carcinoid and pancreatic tumors. The 44-amino-acid forms of GHRH were then first isolated and characterized from human pancreatic tumors that caused acromegaly 3 and GHRH was only subsequently identified from human and animal hypothalami. GHRH belongs to a family of related peptides that includes vasoactive intestinal peptide (VIP), pituitary adenylate cyclaseactivating peptide (PACAP), secretin, glucagon, glucagon-like peptides-1 and -2, and gastric inhibitory peptide. 3 Peptides in this family act to stimulate the intracellular accumulation of cAMP with the resultant activation of protein kinase A. 5,6 The full intrinsic biological activity of GHRH is retained by the *Correspondence to: Andrew V. Schally;
Endocrine Journal, 2000
Growth hormone-secretagogue receptor (GHSR) RNA is known to be expressed in the hypothalamus and pituitary. Since endogenous GH secretagogue (GHS) is still unknown, the physiological role of GHS and GHSR in growth is not well understood. In this study, we have determined the effects of growth hormone in GH-releasing hormone receptor (GHRHR) and GHSR RNA expression in spontaneous Dwarf rats (SDRs) which are deficient in GH secretion, with or without GH replacement. Twenty-five-day-old SDRs received daily s.c. injection of human GH (40pg/kg BW x 2/day) or control solution for two weeks. On day 40, the rats were sacrificed by decapitation and the pituitaries were immediately removed and quickly frozen. Total RNA was extracted from the pituitary, and mRNA coding GHSR was detected and semiquantitated by competitive RT-PCR. Pituitaries from control SDRs showed strong GHSR RNA expression and the expression level was 5 to 10 times higher in females than in males. When GH was replaced, GHSR RNA expression greatly decreased. Pituitary GHRHR RNA expression, determined by RNase Protection Assay, was similar in male and female control animals; and was also greatly reduced in rats treated with GH when compared to the control. These results suggest that the expression of both GHSR and GHRHR is regulated by growth hormone, presumably via changes in hypothalamic GHRH and/or endogenous GHS. The apparent sexual dimorphism in GHSR indicates different regulatory effects of sex steroid in young growing SDRs.
Molecular Endocrinology, 1990
The role of thyroid hormone and GH in the regulation of hypothalamic GH-releasing hormone (GRH) gene expression in the rat was examined after the induction of thyroid hormone deficiency by thyroidectomy. Thyroidectomy resulted in a time-dependent decrease in hypothalamic GRH content, which was significant by 2 weeks postoperatively, and a reduction in pituitary GH content to 1% of the control level by 4 weeks. In contrast, GRH secretion by incubated hypothalami under both basal and K +-stimulated conditions was increased after thyroidectomy. Hypothalamic GRH mRNA levels also exhibited a timedependent increase, which was significant at 1 week and maximal by 2 weeks after thyroidectomy. Administration of antirat GH serum to thyroidectomized rats resulted in a further increase in GRH mRNA levels. T 4 treatment of thyroidectomized rats for 5 days, which also partially restored pituitary GH content, lowered the elevated GRH mRNA levels. However, comparable effects on GRH mRNA levels were observed by rat GH treatment alone. These results suggest that the changes in hypothalamic GRH gene expression after thyroidectomy in the rat are due to the GH deficiency caused by thyroidectomy, rather than a direct effect of thyroid hormone on the hypothalamus, since the changes were reversible by GH alone despite persistent thyroid hormone deficiency. In addition, they further support the role of GH as a physiological negative feedback regulator of GRH gene expression. (Molecular Endocrinology 4: 402-408, 1990) INTRODUCTION