Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth hormone releasing peptide (GHRP-6) is a synthetic hexapeptide which specifically stimulates secretion of growth hormone (GH) by pituitary somatotrophs. The precise intracellular mechanism by which this is achieved has not been deciphered although it is known to involve protein kinase C (PKC) and Ca2+ but to be cAMP-independent. We have used cell cultures of human pituitary somatotrophinomas to demonstrate powerful effects of GHRP-6 on membrane phosphatidylinositol (PI) turnover, a second messenger system which leads to activation of PKC and mobilisation of intracellular Ca2+ reserves. Incubation of somatotrophinoma cells with GHRP-6 led to a dose-dependent stimulation of rate of PI turnover. GH secretion was increased in parallel. Effects were discernable after only 15 minutes incubation and rose to a maximum at 2 hours. PI turnover was stimulated by GHRP-6 in 8 of 8 tumours examined, effects ranging from 2.1 - 7.9 fold increases. Stimulation of GH secretion by GHRP-6 was independent of presence of gsp oncogenes, emphasising the cAMP-independent nature of its effects. These results provide evidence that the GH-stimulatory effects of GHRP-6 are achieved through activation of the PI second messenger system and thus support earlier findings that PKC and Ca2+ play central roles in mediating the effects of GHRP-6.
J Mol Endocrinol 1995 Feb
PMID:Growth hormone releasing peptide (GHRP-6) stimulates phosphatidylinositol (PI) turnover in human pituitary somatotroph cells. 777 38

The effects of the synthetic GH-releasing peptides, GHRP-2 and GHRP-6, on phosphatidylinositol (PI) hydrolysis and cAMP production have been examined in human pituitary somatotropinomas with and without adenylyl cyclase-activating gsp oncogenes. Both peptides dose-dependently stimulated the rate of PI hydrolysis and GH secretion by cell cultures of both types of somatotropinoma. GHRP-2 was considerably more potent than GHRP-6. The effects on GH secretion were reduced or abolished by phloretin, an inhibitor of protein kinase C, and W7, an inhibitor of calmodulin. However, antagonism of the GHRH-receptor and of protein kinase A with (N-Ac-Tyr1,D-Arg2)GRF-(1-29)-NH2 and Rp-adenosine-3',5'-cyclic monophosphothioate, respectively, did not alter the stimulatory effects of GHRP-2 and GHRP-6 on GH secretion. The effect of GHRP-2 and/or GHRP-6 on cAMP production was studied in 15 tumors, seven of which possessed constitutive adenylyl cyclase activity as evidenced by presence of gsp oncogenes. Both peptides stimulated cAMP production in the latter but not former types of tumor. Moreover, GHRP-2 and GHRP-6 potentiated the stimulation of cAMP production induced by GHRH and pituitary adenylate cyclase-activating polypeptide in tumors without gsp oncogenes. These results demonstrate that GHRP-2 and GHRP-6 exert identical effects on human pituitary somatotropinomas, except for differences in potency. Additionally, under conditions of adenylyl cyclase activity above basal levels (i.e. through stimulation of G2-protein coupled receptors or because of gsp oncogene expression), cAMP production can be increased even further by GHRP, providing evidence for cross-talk between the PI and adenylyl cyclase transduction systems in pituitary cells.
Mol Endocrinol 1996 Apr
PMID:Protein kinase C-dependent growth hormone releasing peptides stimulate cyclic adenosine 3',5'-monophosphate production by human pituitary somatotropinomas expressing gsp oncogenes: evidence for crosstalk between transduction pathways. 872 87

The potential application of small molecules in GH therapy has recently become a topic of increasing interest. The spiroindoline MK-0677, the benzolactam L-692,429, and the peptides, GHRP-6 and hexarelin, have been shown to possess potent and selective GH-secretory activity in several species including human. Moreover, these synthetic GH secretagogues act on a signal transduction pathway distinct from that of GHRH. A specific high affinity binding site in porcine and rat anterior pituitary membranes that mediates the activity of these secretagogues has now been identified. The binding affinity of these structurally diverse secretagogues is tightly correlated with GH-secretory activity. The binding is Mg(2+)-dependent, is inhibited by GTP-gamma-S, and is not displaced by GHRH and somatostatin. The receptor is distinct from that for GHRH and has the properties of a new G-protein-coupled receptor. It is speculated that these GH secretagogues mimic an unidentified natural hormone that regulates GH secretion in concert with GHRH and somatostatin.
Mol Endocrinol 1996 Jan
PMID:Identification of a new G-protein-linked receptor for growth hormone secretagogues. 883 45

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 approximately 2 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 [35S]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.
Mol Endocrinol 1997 Apr
PMID:Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. 909 93

Growth hormone-releasing peptides and non-peptides (GHRPs. GHRP-GHS) are a new chemical class of GH secretagogues with a chemistry that ranges from small synthetic peptides to peptidomimetics. They release GH in animals and humans by a unique dual and complementary action on the hypothalamus and pituitary. Although the present GHRPs are of unnatural origin, evidence by a number of investigators is gradually accumulating to support that GHRP reflects the GH-releasing action of a new natural hypothalamic hormone yet to be isolated and identified. Despite the de novo origin of GHRP, a major reason for the persistent investigation is because of the possible practical diagnostic and therapeutic value in humans as well as the potential theoretical value of new insight into the physiological regulation of GH secretion.
Cell Mol Life Sci 1998 Dec
PMID:Growth hormone-releasing peptide (GHRP). 989 8

Fibrin derived from fibrinogen after thrombin cleavage plays an essential role in forming blood clots. Fibrin as well as fibrinogen is also involved in the induction of platelet aggregation, leukocyte cell adhesion and phagocytosis. An additional biological role of fibrin and fibrinogen is presented in this study. One of the proteolytic peptides of fibrin/fibrinogen, fragment E, and not fragment D, was able to stimulate rat peritoneal macrophages to express interleukin-6 (IL-6). The stimulation of fibrin/fibrinogen fragment E on macrophages appeared to work in a dose- and time-dependent manner. Adherent fibrin fragment E was able to stimulate IL-6 expression as well as IL-6 protein production. The effect of fibrin fragment E was inhibited by the addition of an excess amount of GPRP tetrapeptide, but not by GHRP, which are the amino acids derived from the amino terminus of fibrin alpha and beta chains, respectively. These results suggest that fibrin as well as fibrinogen function as a stimulator to macrophages, and leukocyte integrin p150,95 (CD11c/ CD18), not Mac-I (CD11b/CD18), is involved in mediating fibrin stimulatory activity in macrophages.
Mol Cells 1999 Feb 28
PMID:Fragment E derived from both fibrin and fibrinogen stimulates interleukin-6 production in rat peritoneal macrophages. 1010 64

GH secretagogues are an expanding class of synthetic peptide and nonpeptide molecules that stimulate the pituitary gland to secrete GH through their own specific receptor, the GH-secretagogue receptor. The cloning of the receptor for these nonclassical GH releasing molecules, together with the more recent characterization of an endogenous ligand, named ghrelin, have unambiguously demonstrated the existence of a physiological system that regulates GH secretion. Somatotroph cell-specific expression of the GH gene is dependent on a pituitary-specific transcription factor (Pit-1). This factor is transcribed in a highly restricted manner in the anterior pituitary gland. The present experiments sought to determine whether the synthetic hexapeptide GHRP-6, a reference GH secretagogue compound, as well as an endogenous ligand, ghrelin, regulate pit-1 expression. By a combination of Northern and Western blot analysis we found that GHRP-6 elicits a time- and dose-dependent activation of pit-1 expression in monolayer cultures of infant rat anterior pituitary cells. This effect was blocked by pretreatment with actinomycin D, but not by cycloheximide, suggesting that this action was due to direct transcriptional activation of pit-1. Using an established cell line (HEK293-GHS-R) that overexpresses the GH secretagogue receptor, we showed a marked stimulatory effect of GHRP-6 on the pit-1 -2,500 bp 5'-region driving luciferase expression. We truncated the responsive region to -231 bp, a sequence that contains two CREs, and found that both CREs are needed for GHRP-6-induced transcriptional activation in both HEK293-GHS-R cells and infant rat anterior pituitary primary cultures. The effect was dependent on PKC, MAPK kinase, and PKA activation. Increasing Pit-1 by coexpression of pCMV-pit-1 potentiated the GHRP-6 effect on the pit-1 promoter. Similarly, we showed that the endogenous GH secretagogue receptor ligand ghrelin exerts a similar effect on the pit-1 promoter. These data provide the first evidence that ghrelin, in addition to its previously reported GH-releasing activities, is also capable of regulating pit-1 transcription through the GH secretagogue receptor in the pituitary, thus giving new insights into the physiological role of the GH secretagogue receptor on somatotroph cell differentiation and function.
Mol Endocrinol 2001 Sep
PMID:Regulation of Pit-1 expression by ghrelin and GHRP-6 through the GH secretagogue receptor. 1151 97

A review is presented on progress in the research of stimulatory inputs that regulate growth hormone secretion, including recent results on the action of the hypothalamic peptides growth-hormone releasing factor (GHRH) and pituitary adenylate cyclase-activating polypeptide (PACAP), as well as that of both peptidic (growth hormone-releasing hexapeptide; GHRP-6) and non-peptidyl (L-163,255) synthetic GHSs on somatotrope cell function.
Comp Biochem Physiol B Biochem Mol Biol 2002 May
PMID:Research progress in the stimulatory inputs regulating growth hormone (GH) secretion. 1199 17

The aim of this study is to investigate the effects of ghrelin and GH-releasing peptide-6 (GHRP-6) on the release of growth hormone (GH), adrenocorticotrophic hormone (ACTH), and cortisol in dogs with pituitary-dependent hyperadrenocorticism (PDH) and in healthy dogs of comparable age. In eight healthy dogs, the responses to ghrelin and GHRP-6 were compared to those of GH-releasing hormone (GHRH) and NaCl 0.9% (control). In seven dogs with PDH, the effects of ghrelin and GHRP-6 were compared with their effects in healthy dogs. In the healthy dogs, GHRH, GHRP-6, and ghrelin caused a significant rise in plasma GH concentrations. GHRH administration elicited significantly higher plasma GH concentrations than administration of ghrelin and GHRP-6. In the dogs with PDH, the GHRP-6-induced release of GH was significantly lower than in healthy dogs. Administration of ghrelin elicited a GH release that did not differ significantly between dogs with PDH and healthy dogs. Ghrelin and GHRP-6 did not cause a significant rise in plasma ACTH and cortisol concentrations in either the healthy dogs or the dogs with PDH. It is concluded that in comparison with GHRH, GHRP-6 and ghrelin have a low GH-releasing potency in healthy dogs. In dogs with PDH, the GH release in response to GHRP-6 is impaired. Neither GHRP-6 nor ghrelin activates the pituitary-adrenocortical axis in healthy elderly dogs and dogs with PDH.
Mol Cell Endocrinol 2002 Nov 29
PMID:Effects of growth hormone-releasing peptides in healthy dogs and in dogs with pituitary-dependent hyperadrenocorticism. 1243 2

Two cDNA transcripts, namely sbGHSR-1a and sbGHSR-1b, for growth hormone secretagogue receptor (GHSR), were identified from the seabream pituitary. When translated, the sbGHSR-1a encodes for a protein of 385 amino acids (aa) with seven putative transmembrane domains and the sbGHSR-1b contains 295 aa with five putative transmembrane domains. Tissue distribution studies indicated that the two receptors are mainly expressed in the central nervous system of the fish. The sbGHSR-1a transcript has the highest expression level in the pituitary. The sbGHSR-1b transcript, on the other hand, has the highest expression level in the telencephalon. Genomic Southern analysis indicated that there is a single gene for GHSR in the seabream genome. Comparison of the cDNA sequences of sbGHSR1a and sbGHSR1b with the seabream genomic sequence indicated that the presence of the two receptor transcripts is a result of alternative splicing of the single GHSR gene. The two receptor cDNAs were expressed in cultured eukaryotic cells for functional analyses. A variety of structurally diverse growth hormone secretogogues (GHS), including the peptide GHS (GHRP-6 and ghrelin), the benzolactam GHS (L692,585) and the spiropiperidine GHS (L163,255), were able to trigger an elevation of intracellular Ca(2+) ion concentration in HEK293 cells expressing sbGHSR-1a, but not in cells expressing sbGHSR-1b. Microphysiometry revealed that an increase in extracellular acidification rate (EAR) could be detected in CHO cells expressing the sbGHSR-1a receptor when stimulated with GHRP-6. On the contrary, CHO cells expressing the sbGHSR-1b receptor registered no detectable EAR changes. However, when sbGHSR-1b was co-expressed with sbGHSR-1a in HEK293 cells, the signal transduction capacity of sbGHSR-1a was attenuated. This is the first report on the identification of a GHSR-1b transcript from species other than mammals and the demonstration that receptor interaction might provide a possible explanation for the existence and biological significance of the sbGHSR-1b transcript.
Mol Cell Endocrinol 2004 Feb 12
PMID:Identification and functional characterization of two alternatively spliced growth hormone secretagogue receptor transcripts from the pituitary of black seabream Acanthopagrus schlegeli. 1506 47


1 2 3 4 Next >>