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

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

The pathophysiology of mammosomatotroph adenomas remains unclear. We studied a mammosomatotroph adenoma removed from an 8-year old boy with a 5-year history of growth acceleration and acromegalic gigantism at presentation. Elevated basal GH (mean 28 micrograms/l) and PRL (mean 120 micrograms/l) plasma levels were observed, as well as paradoxical responses of GH to L-dopa, TRH and oral glucose administration; PRL was reduced by L-dopa and slightly increased by TRH; GHRH stimulated release of both GH and PRL. Two operations were required to remove the very large tumour and the patient was treated with bromocriptine before the second. Hormonal secretion by tumour explants in culture was evaluated under basal conditions and after stimulation or inhibition. High levels of GH and PRL were secreted for up to 24 days. Furthermore, GHRH and TRH caused a dose-related stimulation of both hormones, while somatostatin and dopamine were effective in suppressing either basal or stimulated hormone release only at very high (microM) concentrations. Intracellular events were studied by determination of the guanosine triphosphate binding (G) protein levels and adenylate cyclase (AC) activity in the tumour tissue. Before bromocriptine treatment, AC activity was very high in the tumour and could be further stimulated by various agents; very high levels of the AC-stimulatory G protein alpha subunit Gs alpha and very low amounts of the AC-inhibiting G protein alpha subunit Gi3 alpha and of the phospholipase C-stimulating G protein alpha subunit Gq alpha were found in the tumour. After bromocriptine, baseline AC activity was normalized and could no longer be stimulated; Gs alpha and Gi3 alpha levels were unchanged while those of Gq alpha were normalized. Screening of tumour DNA after amplification by polymerase chain reaction followed by single-strand conformational polymorphism analysis did not reveal any mutations in the hot spots of G protein alpha subunits (alpha s, alpha i2, alpha o2 and alpha 11) genes or in the H-ras and p53 genes. Gs alpha and GH transcription factor-1 (pit-1) expression were evaluated by amplification of cDNA. While the mRNA expression of pit-1 decreased after bromocriptine treatment, that of Gs alpha increased. These data suggest the possibility of an oncogenic process involving overexpression of Gs alpha, resulting in chronic activation of adenylate cyclase. Furthermore, our results suggest that the anti-secretory and anti-proliferative effects of bromocriptine may be mediated through a decrease in Pit-1 secondary to the inhibition of adenylate cyclase activity.
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PMID:Mammosomatotroph adenoma causing gigantism in an 8-year old boy: a possible pathogenetic mechanism. 762 75

Pituitary adenylate cyclase activating polypeptide (PACAP) is a new member of the secretin/glucagon/vasoactive intestinal peptide (VIP) family. It stimulates adenylate cyclase in cultured rat pituitary cells, which have PACAP-specific receptors and expression of pituitary hormones. Therefore, PACAP is considered as a hypophysiotropic hormone. If so, there might be a feedback regulatory mechanism between pituitary hormones and hypothalamic PACAP. In the present study, we used nuclear run-on and RNase protection assays to examine whether transcription of the PACAP gene in the rat hypothalamus would change after hypophysectomy. PACAP levels in the hypothalamus were also determined by radioimmunoassay. The transcriptional rate of the PACAP gene and PACAP mRNA content decreased 1 and 2 weeks after hypophysectomy. Radioimmunoassayable PACAP levels in the hypothalamus also decreased after hypophysectomy. These findings suggest that the reduced rate of PACAP gene transcription after hypophysectomy causes the decreased mRNA and peptide levels in the hypothalamus. Replacement with GH, PRL, T4, corticosterone, and testosterone significantly restored PACAP mRNA levels in hypophysectomized rats to those in control animals. The results suggest that feedback regulation takes place between pituitary hormones or pituitary-dependent factors and hypothalamic PACAP.
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PMID:Effect of hypophysectomy on pituitary adenylate cyclase activating polypeptide gene expression in the rat hypothalamus. 765 92

GH3 cells, which normally release PRL in response to stimulation by TRH, have been stably transfected with rat GnRH receptor complementary DNA (GGH3-1' cells). Unlike the parent line, GGH3-1' cells express GnRH receptor, which can be measured in a radioligand assay using a metabolically stable GnRH analog. The number of receptors (11,000 +/- 2,800 receptors/cell; n = 3) and Kd (4.1 +/- 1.0 x 10(-8) M; n = 3), determined using a radioiodinated GnRH agonist, as well as binding inhibition values for GnRH agonists and antagonists and for unrelated substances suggest that this receptor is similar to those expressed in cell cultures derived from rat pituitaries, although the binding affinity is about 1 log lower in the former. Unlike GnRH-stimulated release of gonadotropins from primary pituitary cultures, which does not require protein synthesis and is not coupled to cAMP production, GnRH-stimulated PRL release from the transfected cell line is absolutely dependent on protein synthesis, and cAMP fulfills the requirements of a second messenger. The receptor appears to be coupled to adenylate cyclase-mediated PRL release through a cholera toxin-sensitive G-protein. These studies provide functional evidence to support the view that the cloned receptor is the physiological receptor for the releasing hormone, and that this receptor can differentially couple to G-proteins depending on their availability and accessibility in the target cell.
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PMID:Stable transfection of GH3 cells with rat gonadotropin-releasing hormone receptor complementary deoxyribonucleic acid results in expression of a receptor coupled to cyclic adenosine 3',5'-monophosphate-dependent prolactin release via a G-protein. 801 67

The presence of pituitary adenylate cyclase activating polypeptide (PACAP) receptors coupled to adenylate cyclase was investigated in four types of human pituitary adenomas: three null adenomas and five gonadotropin-, three ACTH-, four GH-, and four PRL-producing adenomas. In all samples, except in prolactinomas, PACAP(1-27) and PACAP(1-38) stimulated adenylate cyclase activity equally well and potently (K(act) around 3 nmol). Vasoactive intestinal polypeptide (VIP) was systematically 100- to 300-fold less potent than both PACAPs. In prolactinomas, PACAP(1-27), PACAP(1-38), and VIP were inactive despite a response of the enzyme to guanosine 5'-triphosphate, Gpp(NH)p, forskolin, and fluoride. [125I-AcHis1]PACAP(1-27) binding was detected in all samples except in prolactinomas. In addition, a detailed analysis of receptors was feasible in all five gonadotropin- and in two ACTH-producing adenomas, confirming the existence of selective PACAP receptors that recognized PACAP(1-27) and PACAP(1-38) with similar high affinity (IC50 0.8-1.5 nmol) and VIP with a low affinity (IC50 100 nmol/L).
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PMID:Receptors for pituitary adenylate cyclase activating peptides in human pituitary adenomas. 807 16

We previously reported that a factor(s) from rat choriocarcinoma (Rcho-1) cells suppresses circulating PRL levels and increases tyrosine hydroxylase activity in tuberoinfundibular dopaminergic neurons in vivo. The purposes of this study were to determine whether this factor(s) increases tyrosine hydroxylase activity in fetal hypothalamic cells in vitro and to evaluate its chemical nature. The Rcho-1 cells are of placental origin and have the capacity to differentiate into giant cells and produce members of the placental PRL family. MMQ cells, a pituitary cell line that secretes PRL, and HRP-1, a placental cell line that does not produce any known members of the PRL family, were used as control cells. Tyrosine hydroxylase activity was assessed by incubation of hypothalamic cells for 1 h with 100 microM brocresine, an inhibitor of aromatic L-amino acid decarboxylase. Tyrosine hydroxylase activity was increased in a density-dependent manner when Rcho-1, but not HRP-1 or MMQ, cells were cocultured with hypothalamic cells for 24 h. Control and Rcho-1-stimulated tyrosine hydroxylase activities were markedly reduced with 1 mM alpha-methyl-p-tyrosine, a specific inhibitor of tyrosine hydroxylase. Tyrosine hydroxylase activity was not altered when hypothalamic cells were incubated for 24 h with rat PRL or recombinant rat placental lactogen-I, whereas a 24-h stimulation with 100,000 Rcho-1 cells and a 1-h stimulation with 5 mM (Bu)2cAMP increased tyrosine hydroxylase activity 3.7- and 3-fold, respectively. The magnitudes of the increase in tyrosine hydroxylase activity were similar when hypothalamic cells were cocultured with Rcho-1 cells for 1 and 24 h. Acetic acid extracts of Rcho-1, but not HRP-1 or MMQ, cells increased tyrosine hydroxylase activity within 1 h in a concentration-dependent manner. The 3-fold increase in tyrosine hydroxylase activity observed with 500,000 Rcho-1 cell equivalents was markedly reduced with 1 mM alpha-methyl-p-tyrosine. The mol wt range of the tyrosine hydroxylase-activating factor(s) (THAF) was estimated using ultrafiltration membranes. The majority of activity was found in the eluate from a 1,000 mol wt cut-off membrane. THAF activity in Rcho-1 cell extracts was decreased by preincubation with pronase, a nonspecific proteolytic enzyme, suggesting that the factor(s) is a peptide. THAF was resistant to inactivation by trypsin or chymotrypsin pretreatment. However, both enzymes destroyed the ability of pituitary adenylate cyclase-activating peptide, either alone or with Rcho-1 cell extracts, to increase tyrosine hydroxylase activity. Oxidation of Rcho-1 cell extracts with performic acid abolished THAF activity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A factor(s) from a trophoblast cell line increases tyrosine hydroxylase activity in fetal hypothalamic cell cultures. 810 May 18

Among vertebrates, there is an extreme conservation in amino acid sequence for the neuropeptide PACAP-38 and its C-terminal shortened derivative PACAP-27. The PACAP gene is assigned to chromosome 18 in man and its organization has been characterized. PACAP-38 and its minor derivative PACAP-27 are widely distributed in the central nervous system. PACAP-38 is particularly abundant in hypothalamus. The mapping of the afferentation and efferentation of PACAP systems are progressively delineated, including a search for the colocalization with other neurotransmitters. In several peripheral organs positive neuronal perikarya and fibers are also seen. PACAP acts through two types of receptors: (1) the highly selective type I that displays a 500 to 2000 selectivity for PACAP-38 and PACAP-27 as compared to VIP; (2) type II is the so-called VIP receptor showing similar high affinity for PACAP-38, PACAP-27 and VIP. It is less selective, therefore, than previously thought. This is why this second receptor, qualifying as an unspecific VIP-PACAP receptor, is hardly considered here. Type I receptors can stimulate two enzymes: the adenylate cyclase and phospholipase C (whose activation leads to the inositol phosphate-cytosolic Ca2+ cascade). This dual coupling may have several distal consequences including on gene expression, cell growth and differentiation. Although a relatively comprehensive spectrum of pharmacological activities has already been established we still need to limit the physiological roles of PACAP as neurotransmitter and/or neuromodulator. Concerning the hypothalamo-pituitary axis, PACAP reduces food intake in mice and raises plasma arginine vasopressin in rat, probably through PACAP-ir neurons in paraventricular and supraoptic nuclei projecting to the neurohypophysis. PACAP originating in the hypothalamus may also be transported to the anterior pituitary through portal vessels. Data on the antehypophysis suggest a role on i.a. reproduction and growth. PACAP stimulates adenylate cyclase and increases [Ca2+] in gonadotropes, somatotropes, and folliculo-stellate cells. It elevates the secretion of alpha-MSH from melanotropes, and that of interleukin-6 from pituitary folliculo-stellate cells. PACAP potentiates the effects of LHRH on LH and FSH secretion. More clearly perhaps, PACAP increases the synthesis of LH, GH, PRL and ACTH after 1-2 days. In human pathology, PACAP-27 and PACAP-38 stimulate adenylate cyclase activity in membranes from 'null'-, gonadotropin-, GH-, and ACTH-producing pituitary adenomas but are inactive in prolactinomas.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Type I receptors for PACAP (a neuropeptide even more important than VIP?). 821 37

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to activate adenylate cyclase and stimulate PRL secretion in dispersed pituitary cells. We have employed the GH3 rat pituitary cell line to investigate whether PACAP can regulate expression of the PRL gene. PACAP increased cellular levels of cAMP in a concentration-dependent fashion (EC50, approximately 6 x 10(-9) M). PACAP also increased PRL mRNA levels in GH3 cells, implying that this peptide stimulates a step in expression of the PRL gene. In addition, PACAP strongly stimulated chloramphenicol acetyltransferase (CAT) activity in GH3 cells transiently transfected with a plasmid containing the first 187 basepairs of the rat PRL promoter cloned up-stream of the CAT gene, implying that PACAP stimulates transcription directed by the PRL promoter. The PACAP stimulation of CAT activity was observed at concentrations as low as 10(-11) M. We examined the action of PACAP on expression of a 5'-deletion series of PRL-CAT constructs. The PACAP response is completely lost when PRL promoter sequences between positions -187 and -113 are removed, implying that neither a previously described sequence resembling a cAMP response element nor the most proximal pit-1-binding site 1P plays a major role in the actions of PACAP on PRL gene transcription. This observation together with the ability of low concentrations of PACAP to stimulate PRL promoter activity without detectably increasing cellular cAMP levels suggest that the action of PACAP on PRL gene transcription might involve a cAMP-independent pathway.
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PMID:Pituitary adenylate cyclase-activating polypeptide stimulates prolactin gene expression in a rat pituitary cell line. 824 97

Two novel peptides, named PACAP (pituitary adenylate cyclase activating polypeptide) containing 38 (PACAP38) and 27 residues (PACAP27) were recently isolated from ovine hypothalami. In order to investigate the pituitary cell type(s) that bear a receptor for PACAP, PACAP38 was biotinylated and used for cytochemical examination of binding. The cells were also identified by immunocytochemical methods using the antisera against each of the rat anterior pituitary hormones or an antiserum against S-100 protein, a marker for pituitary folliculo-stellate (FS) cells. Biotinylated PACAP38 (biot-PACAP) exhibited adenylate cyclase stimulating activity (ACSA) comparable to PACAP38 in rat pituitary cell cultures, and displaced the bound 125I-PACAP27 to the rat pituitary membrane preparation to the same extent as PACAP38. After 2-4 days of culture, dispersed rat pituitary cells were incubated with varying concentrations of biot-PACAP at room temperature or 4 degrees C. The bound biot-PACAP38 was visualized by avidin-biotin-peroxidase complex (ABC) method with nickel intensification. Biot-PACAP-positive and pituitary hormone or S-100-positive cells were counted. More than 90% of S-100-positive cells bound biot-PACAP38. A considerable number of GH and PRL cells and a lesser number of ACTH cells also bound biot-PACAP38, whereas only a few identified LH, FSH, or TSH cells bound biot-PACAP38. These results suggest that FS cells are a major target cell type for PACAP. A recent study from our laboratory demonstrated that PACAP stimulated the release of interleukin (IL)-6 in rat pituitary cell cultures. FS cells are known to produce IL-6.
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PMID:Cytochemical characterization of anterior pituitary target cells for the neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP), using biotinylated ligands. 844 7

The capability of rat pituitary cells to express receptors for pituitary adenylate cyclase activating polypeptide (PACAP) and VIP was evaluated by binding studies and measurement of adenylate cyclase activity on whole gland preparations and by reverse transcriptase-polymerase chain reaction (TR-PCR) using specific primers on preparations from isolated cell populations enriched in PRL- and GH-producing cells. Data obtained on whole gland preparations indicated that selective PACAP receptors (PACAP Type I) predominated. The mRNA coding for PACAP Type I and for the non-selective PACAP receptors Type II VIP2 (but not VIP1) were identified. The mRNA coding for four different spliced variants of the PACAP Type I receptor were detected. In PRL producing cells, three variants and the VIP2 mRNA were detected, whereas in GH-producing cells the mRNA coding for the variant having a 28-amino acid insert (termed HOP) in the third intracellular loop was the only present.
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PMID:Differential alternative splicing of PACAP receptor in pituitary cell subpopulations. 867 20

The present investigation was designed to study the direct role of PRL on testicular Leydig cell steroidogenesis, using the MA-10 murine Leydig tumor cell line as a model system. We have previously reported on the presence of specific PRL binding sites in those cells, and we now demonstrate the functionality of those sites and the biological responses induced by the binding of PRL. When cultured MA-10 cells were exposed for 24 h to increasing concentrations of PRL, washed, and then subjected to a 3-h human CG (hCG) stimulation test, a clear dose-dependent biphasic effect of PRL on the steroidogenic response was observed, even though PRL had no effect on MA-10 cell proliferation: at low PRL concentrations (0.1-10 ng/ml), hCG-induced steroidogenesis was stimulated (maximal stimulation by 1 ng/ml PRL being 200-250% of control); at higher concentrations, hCG-induced steroidogenesis was inhibited (60% inhibition was achieved by 1000 ng/ml PRL). When steroidogenesis was induced with various concentrations of cholera toxin, instead of hCG, no effect of the prior exposure to increasing concentrations of PRL was observed, indicating that PRL acts either at the level of the LH/hCG receptor or at some stage proximal to adenylate cyclase. Indeed, further study revealed that 24 or 72 h exposure of MA-10 cells to PRL caused a dose-dependent reduction in hCG binding. Thus, the maximal inhibition of 62% after 72 h with 500 ng/ml PRL, may explain, at least in part, the inhibitory effects of high PRL concentrations on hCG-induced progesterone secretion. Evidence demonstrating possible involvement of a pertussis toxin-(PT-)sensitive G protein in the signal transduction mechanism of PRL receptors is also presented: 1. GTP caused a dose-dependent reduction in affinity (Ka) of PRL binding by its receptors (from Ka = 1.66 +/- 0.2 x 10(9) M(-1) for control MA-10 cell membranes to Ka 3.03 +/- 0.6 x 10(8) M(-1) for membranes incubated with 8 mM GTP). 2. Prior exposure of MA-10 cells to PRL (10 pg/ml) caused a significant reduction in the ability of a 44-kDa membrane protein to undergo PT-induced [32P]ADP-ribosylation. These results demonstrate that MA-10 Leydig cells possess highly specific and biologically functional PRL receptors mediating direct and dose-dependent biphasic effects of PRL on hCG-induced progesterone secretion. These cells thus offer a suitable model to study the mechanism(s) of PRL action and signal transduction of its receptor on a physiologically relevant differentiated function.
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PMID:Prolactin and MA-10 Leydig cell steroidogenesis: biphasic effects of prolactin and signal transduction. 894 Mar 78


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