Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GRF promotes follicular maturation and ovulation when administered with FSH in the treatment of infertility. Such actions could be mediated by stimulation of GH secretion and insulin-like growth factor I production, but the known actions of the structurally related hormone, vasoactive intestinal peptide (VIP), on granulosa cell function suggested that GRF may also act directly on the ovary to stimulate follicular development. Radioligand binding and activation studies, performed in granulosa cells from immature estrogen-treated rats, revealed a common receptor for VIP and rat (r) GRF in the ovary. Specific binding of [125I]VIP to granulosa cells was saturable and dependent on time and temperature. The relative potencies of VIP-related peptides for inhibition of radioligand binding were: VIP greater than rGRF greater than peptide histidine isoleucinamide greater than [His1,Nle27] human GRF(1-32)NH2 greater than secretin. In binding studies with the potent GRF agonist, [125I] [His1,Nle27]GRF(1-32)NH2, relative potencies were: rGRF(1-43)OH greater than [His1,Nle27]human GRF(1-32)NH2 greater than VIP greater than peptide histidine isoleucinamide greater than secretin. Glucagon and gastric inhibitory peptide, other peptides of the glucagon superfamily, and unrelated peptides including CRF and beta-endorphin, did not inhibit binding of either radioligand to ovarian receptors. In cultured granulosa cells, rGRF and VIP stimulated cAMP formation, consistent with coupling of their receptors to the adenylate cyclase system, and potentiated FSH-induced cAMP production. Both peptides also amplified FSH-induced progesterone biosynthesis, aromatase activity, and LH receptor formation. These observations demonstrate that rGRF is a potent cAMP-mediated agonist in the rat ovary and acts on a common VIP/GRF receptor in maturing granulosa cells. It is likely that the potentiating effect of administered GRF on gonadotropin-stimulated follicular development in vivo is in part mediated by direct actions of the peptide on the VIP/GRF receptor. Also, since GRF is present in the gonads, it is possible that the locally-produced peptide promotes follicular maturation by paracrine modulation of the stimulatory action of FSH on granulosa cell function.
...
PMID:Receptor-mediated actions of growth hormone releasing factor on granulosa cell differentiation. 217 7

The correlation between response of plasma GH to GHRH and the GHRH-induced stimulation of the intracellular adenylate cyclase (AC) activity in pituitary adenoma cell membranes in acromegalic patients was investigated. Each peak plasma GH level after iv administration of GHRH ranged from 1.1 to 13.8 times the basal level in 13 acromegalic patients. On the other hand, the maximal stimulation of intracellular AC activity (cAMP production) induced by GHRH varied from 1.4 to 6.4 times the control level in each GH-producing pituitary adenoma cell membrane. A significant positive correlation (r = 0.89, P less than 0.005) between plasma GH response to GHRH and intracellular cAMP production stimulated by GHRH was observed in nine of the acromegalic patients. In contrast, the response of plasma GH to GHRH was significantly blunted, despite a fairly large production of intracellular cAMP stimulated by GHRH, in the other four acromegalic patients. These results suggest that GHRH-induced GH release from GH-producing pituitary adenomas of patients with acromegaly may be regulated not only by GHRH receptor-adenylate cyclase system but also modified by several other factors including somatostatin and Sm-C.
...
PMID:Growth hormone releasing hormone-sensitive adenylate cyclase activity in growth hormone-producing pituitary adenoma: correlation to the response of plasma growth hormone to growth hormone releasing hormone in patients with acromegaly. 255 Feb 7

The ability of 30 synthetic GRF(1-29)-NH2 analogs to stimulate adenylate cyclase activity was investigated in membranes from rat adenopituitary, rat liver and rat pancreas. In adenopituitary membranes, GRF and GRF analogs interacted with specific GRF receptors, whereas in liver and pancreatic membranes, they interacted with VIP receptors. The C-terminal moiety of GRF was responsible for GRF receptor recognition as the hybrid analog (His1, D-Ala2)-GRF(1-9), VIP(10-28) stimulated pituitary adenylate cyclase through the occupancy of VIP receptors only. When GRF or VIP receptors were occupied by GRF analogs, the N-terminal part of the ligand appeared critical for adenylate cyclase activation. This was established by testing 30 GRF analogs mono-, bi- or tri-substituted in positions 1 to 10. Major observations included: (a) the characterization of (N-Ac-Tyr1, D-Arg2)-GRF(1-29)-NH2 as an antagonist of GRF-stimulated pituitary adenylate cyclase; (b) the discovery of the (N-Ac-Tyr1, D-Phe2)-, (His1, D-Ala2, D-Ser3, NLeu27)-, and (His1, D-Ala2, D-Thr7, NLeu27)-derivatives of GRF(1-29)-NH2 as specific antagonists of VIP receptors in rat pancreatic membranes; (c) the importance of the free NH2 function of amino acid residue 1 for pancreatic adenylate cyclase activation, and (d) the decreased efficiency of iodinated (Tyr1)-GRF(1-29)-NH2 as opposed to the non iodinated form, in all systems tested.
...
PMID:Comparative structural requirements of thirty GRF analogs for interaction with GRF- and VIP receptors and coupling to adenylate cyclase in rat adenopituitary, liver and pancreas. 301 3

Pituitary tumorigenesis is characterized by initiation, implying spontaneous or acquired mutations and promotion, implying that tumour expansion is sustained by intrinsic or extrinsic promoting factors. Pituitary tumours have a doubling time of 100 to 700 days. Seventy per cent of cases occur in 30 to 50-year-old patients, but tumours with highest growth rate (prolactin and ACTH-secreting adenomas) are also encountered in patients < 20 years. Pituitary adenomas occur at a greater frequency in females but there is no vivo evidence for a direct role of sex hormones. Oestrogen can amplify tumour growth factors in pituitary cell lines. One-third of GH-secreting adenomas have elevated cAMP resting levels which appear to be caused by a somatic mutation in the Gs protein associated with the GHRH receptor. This maintains the adenylate cyclase system in a turned-on state. Patients with mutant Gs protein have higher GH levels, reduced GHRH response, elevated TRH response, good suppressibility by SRIH and smaller tumour size compared to other acromegalic patients. Hypothalamic releasing hormones may be able to sustain pituitary tumour development since some acromegalic patients with GHRH-secreting tumours may harbour a pituitary GH-secreting adenoma. A lack of inhibitory factors may also have a promoting role in tumour progression.
...
PMID:Epidemiology and pathogenesis of pituitary adenomas. 839 32

Growth hormone-releasing hormone (GHRH) belongs to the family of gut-neuropeptide hormones which also includes glucagon, secretin and vasoactive intestinal peptide (VIP). All receptors for this peptide hormone family seem to involve similar signal transduction pathways. Upon hormone binding, these receptors interact with guanine nucleotide binding protein 'Gs' and cause the stimulation of adenylate cyclase. The secretin and VIP receptor cDNAs have recently been cloned and found to be homologous to those of calcitonin and parathyroid hormone receptors. Based on cDNA sequences of these receptors, we designed several oligonucleotide primers which were used to amplify two novel porcine pituitary cDNA fragments by the polymerase chain reaction. One novel receptor cDNA fragment was used to screen a porcine pituitary cDNA library and a full-length cDNA encoding a putative porcine GHRH receptor of 451 amino acids was isolated. This putative receptor mRNA is present specifically in porcine anterior pituitary cells and not in eight other porcine tissues as shown by Northern hybridization analysis. The receptor cDNA was subsequently cloned into a mammalian cell expression vector containing the cytomegalovirus promoter. A human kidney tumor cell line (293) stably transfected with this vector was found to express the receptor efficiently and to bind [125I]-GHRH specifically. Furthermore, challenge of the 293 cells expressing the receptor by GHRH leads to efficient stimulation of cytoplasmic cAMP production.
...
PMID:Structure and functional expression of a complementary DNA for porcine growth hormone-releasing hormone receptor. 841 47

Many important advances in our understanding of the growth hormone (GH) axis have occurred during the last decade. A number of neurotransmitters and neuropeptides are implicated in the control of growth hormone-releasing hormone (GHRH) and somatostatin release; however, the role of many of these, such as serotonin, gamma-aminobutyric acid and dopamine, is still a matter of discussion. As a newly isolated hypothalamic peptide with a possible role in the control of GH secretion, pituitary adenylate cyclase activating peptide has received considerable attention. Synthetic hexapeptides that stimulate GH release (GH-releasing peptides 1, 2 and 6) have been identified. Pituitary-specific transcription factors involved in the expression of the GH gene have been identified, the GHRH receptor gene has been cloned, as well as a number of somatostatin receptor genes, and advances in our understanding of the insulin-like growth factor-binding proteins, and growth hormone-binding proteins have been made.
...
PMID:The growth hormone axis: control and effects. 880 20

Repeated stimulation of pituitary cell cultures with GH-releasing hormone (GHRH) results in diminished responsiveness, a phenomenon referred to as homologous desensitization. One component of GHRH-induced desensitization is a reduction in GHRH-binding sites, which is reflected by the decreased ability of GHRH to stimulate a rise in intracellular cAMP. In the present study, we sought to determine if homologous down-regulation of GHRH receptor number is due to a decrease in GHRH receptor synthesis. To this end, we developed and validated a quantitative RT-PCR assay system that was capable of assessing differences in GHRH-R messenger RNA (mRNA) levels in total RNA samples obtained from rat pituitary cell cultures. Treatment of pituitary cells with GHRH, for as little as 4 h, resulted in a dose-dependent decrease in GHRH-R mRNA levels. The maximum effect was observed with 0.1 and 1 nM GHRH, which reduced GHRH-R mRNA levels to 49 +/- 4% (mean +/- SEM) and 54 +/- 11% of control values, respectively (n = three separate experiments; P < 0.05). Accompanying the decline in GHRH-R mRNA levels was a rise in GH release; reaching 320 +/- 31% of control values (P < 0.01). Because of the possibility that the rise in medium GH level is the primary regulator of GHRH-R mRNA, we pretreated pituitary cultures for 4 h with GH to achieve a concentration comparable with that induced by a maximal stimulation with GHRH (8 micrograms GH/ml medium). Following pretreatment, cultures were stimulated for 15 min with GHRH and intracellular cAMP accumulation was measured by RIA. GH pretreatment did not impair the ability of GHRH to induce a rise in cAMP concentrations. However, as anticipated, GHRH pretreatment (10 nM) significantly reduced subsequent GHRH-stimulated cAMP to 46% of untreated controls. These data suggest that GHRH, but not GH, directly reduces GHRH-R mRNA levels. To determine whether this effect was mediated through cAMP, cultures were treated with forskolin, a direct stimulator of adenylate cyclase. Forskolin (10 microM) significantly reduced GHRH-R mRNA concentrations (37 +/- 6% of control values) indicating that GHRH acts through the cAMP-second messenger system cascade to regulate GHRH-R mRNA. The somatostatin analogue, octreotide (10 nM), which has been previously reported to decrease adenylate cyclase activity, did not affect GHRH-R mRNA levels. Taken together, these results indicate that GHRH inhibits the production of its own receptor by a receptor-mediated, cAMP-dependent reduction of GHRH-R mRNA accumulation.
...
PMID:Homologous down-regulation of growth hormone-releasing hormone receptor messenger ribonucleic acid levels. 904 9

The hypothalamic peptide GH-releasing hormone (GHRH) stimulates the release of GH from the pituitary through binding and activation of the GHRH receptor, which belongs to the family of G protein-coupled receptors. The objective of this study was to identify regions of the receptor critical for interaction with the ligand by expressing and analyzing truncated and chimeric epitope-tagged GHRH receptors. Two truncated receptors, GHRHdeltaN, in which part of the N-terminal domain between the putative signal sequence and the first transmembrane domain was deleted, and GHRHdeltaC, which was truncated downstream of the first intracellular loop, were generated. Both the receptors were deficient in ligand binding, indicating that neither the N-terminal extracellular domain (N terminus) nor the membrane-spanning domains with the associated extracellular loops (C terminus) are alone sufficient for interaction with GHRH. In subsequent studies, chimeric proteins between the receptors for GHRH and vasoactive intestinal peptide (VIP) or secretin were generated, using the predicted start of the first transmembrane domain as the junction for the exchange of the N terminus between receptors. The chimeras having the N terminus of the GHRH receptor and the C terminus of either the VIP or secretin receptor (GNVC and GNSC) did not bind GHRH or activate adenylate cyclase after GHRH treatment. The reciprocal chimeras having the N terminus of either the VIP or secretin receptors and the C terminus of the GHRH receptor (VNGC and SNGC) bound GHRH and stimulated cAMP accumulation after GHRH treatment. These results suggest that although the N-terminal extracellular domain is essential for ligand binding, the transmembrane domains and associated extracellular loop regions of the GHRH receptor provide critical information necessary for specific interaction with GHRH.
...
PMID:Identification of binding domains of the growth hormone-releasing hormone receptor by analysis of mutant and chimeric receptor proteins. 960 37

The effects of a GH secretagogue, L-692,585 (L-585), and human GH-releasing hormone (hGHRH) on calcium transient and GH release were investigated in isolated porcine pituitary cells using calcium imaging and the reverse hemolytic plaque assay (RHPA). Somatotropes were functionally identified by the application of hGHRH. All cells that responded to hGHRH responded to L-585 application. Perfusion application of 10 microM hGHRH and L-585 for 2 min resulted in an increase in intracellular calcium concentrations ([Ca(2+)](i)) of 53+/-1 nM (mean+/-S.E.M.) (P < 0.01) and 68+/-2 nM (P < 0.01) respectively. The L-585 response was characterized by an initial increase in [Ca(2+)](i) followed by a decline to a plateau level above the baseline. Concurrent calcium imaging with RHPA indicated that the L-585-evoked increase in [Ca(2+)](i) coincided with GH release. L-585 significantly increased the percentage of plaque-forming cells (24+/-3 vs 40+/-6%; P < 0.05) and mean area of plaques (1892+/-177 vs 3641+/-189 micro m(2); P < 0.01) indicating increased GH release. Substance P (SP) analogue ([d -Arg(1),d -Phe(5),d -Trp(7,11)]-SP) blocked, and the hGHRH receptor antagonist ((Phenylac-Tyr(1),d -Arg(2), p-chloro-Phe(6), Homoarg(9), Tyr (Me)(10), Abu(15), Nle(27),d -Arg(28), Homoarg(29))-GRF (1-29) amide) decreased the stimulatory effect of hGHRH. These failed to block the stimulatory effect of L-585, suggesting a different receptor for L-585 from the GHRH receptor. The hGHRH-induced calcium transients and initial peak increase induced by L-585 were significantly decreased by removal of calcium from the bathing medium or the addition of nifedipine, an L-calcium channel blocker. The plateau component of L-585-induced calcium change was abolished by removal of calcium and nifedipine. These results suggest an involvement of calcium channels in GH release. Either SQ-22536, an adenylate cyclase inhibitor, or U73122, a phospholipase C (PLC) inhibitor, blocked the stimulatory effects of hGHRH and L-585 on [Ca(2+)](i) transient, indicating the involvement of adenylate cyclase-cAMP and PLC-inositol triphosphate pathways. These results further suggested that calcium mobilization from internal stores during the first phase of the L-585 response induced an increase in [Ca(2+)](i) whereas calcium influx during the second phase is a consequence of somatotrope depolarization.
...
PMID:Mechanism of action of the growth hormone secretagogue, L-692,585, on isolated porcine somatotropes. 1247 74

Secretion of GH by pituitary somatotropes is primarily stimulated by the hypothalamic GHRH through the activation of a specific G protein-coupled receptor, GHRH receptor (GHRH-R). GH is also released in response to ghrelin, a peptide produced in the stomach, hypothalamus, and pituitary that activates somatotropes via a distinct G protein-coupled receptor, referred to as the GH secretagogue receptor (GHS-R). Here, we have analyzed the expression of both GHRH-R and GHS-R (by multiplex RT-PCR) in porcine pituitary cell cultures, after acute (4 h) treatment with GHRH or ghrelin as well as with other regulators of somatotropes (somatostatin, dexamethasone). Exposure of cultures to GHRH decreased GHRH-R mRNA content and also diminished GHS-R transcript levels. Likewise, ghrelin down-regulated both GHS-R and GHRH-R expression. Interestingly, administration of the activator of adenylate cyclase, forskolin, decreased GHRH-R mRNA levels but had no effect on GHS-R, thus suggesting a distinct contribution of the various intracellular signals operating in somatotropes to the regulation of the expression of these receptors. Accordingly, an atypical activator of adenylate cyclase in the pig somatotrope is low-dose (10(-13) m) somatostatin, which also suppressed GHRH-R mRNA levels without altering GHS-R expression. Finally, dexamethasone did not modify GHRH-R or GHS-R expression. In summary, our data show for the first time that ghrelin, as well as GHRH, mediates homologous and heterologous down-regulation of their own receptor synthesis. 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.
...
PMID:Homologous and heterologous regulation of pituitary receptors for ghrelin and growth hormone-releasing hormone. 1504 57


1 2 Next >>

---