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)

Neurotransmitters act as trophic factors during brain development, regulating expression of genes that control cellular differentiation. One example of this trophism is the beta adrenergic signaling cascade: activation of beta receptors leads sequentially to increased cyclic AMP (cAMP), augmented expression of the nuclear transcription factor, c-fos, and induction of ornithine decarboxylase (ODC), an enzyme obligatory for neuronal development. After neonatal lesioning of noradrenergic nerves with 6-hydroxydopamine (6-OHDA), beta receptors become uncoupled from ODC induction in the cerebellum, a region that undergoes its peak of cell replication/differentiation postnatally. The present study investigates the mechanism for uncoupling of beta receptors from response elements. In the cerebellum, 6-OHDA had minor effects on beta receptor binding capabilities and caused slight supersensitivity of the beta adrenergic response of adenylate cyclase; the latter reflected increased expression of cyclase catalytic subunits, rather than a specific effect on beta receptor coupling. In contrast, the linkage of cAMP to cerebellar c-fos expression showed marked deficiencies in lesioned animals and a corresponding loss of the ability of beta receptors to induce c-fos; accordingly, this is a likely point at which beta adrenergic control of ODC is programmed by neuronal input. A critical period exists for neurotrophic influence: the alterations persisted past the point at which cerebellar norepinephrine levels recovered, and comparable effects did not occur in earlier-developing regions. In the forebrain, for example, neonatal lesions produced receptor upregulation and supersensitivity of c-fos to cAMP stimulation. These results suggest that presynaptic input is vital in programming beta adrenergic responsiveness during a critical period of development, and that interruption of transsynaptic events occurring at this time can lead to lasting alterations in neuronal differentiation and responsiveness.
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PMID:Role of presynaptic input in the ontogeny of adrenergic cell signaling in rat brain: beta receptors, adenylate cyclase and c-fos protooncogene expression. 771 97

Previous reports have demonstrated that glutamate stimulates c-fos mRNA expression in primary cultures of mouse cerebral cortical neurons. We show here that vasoactive intestinal peptide (VIP) induces c-fos mRNA expression; however, this effect of VIP is completely inhibited by the noncompetitive NMDA receptor antagonist MK-801, therefore indicating that VIP stimulates c-fos expression in a glutamate-dependent manner. A similar effect was observed with pituitary adenylate cyclase-activating polypeptide27 (PACAP27). At the intracellular level, coactivation of protein kinases A and C mediates the glutamate-dependent stimulation of c-fos expression evoked by VIP, because either H-89 or staurosporin inhibits the effect of VIP as well as that of glutamate. These results point to a "biochemical AND gate" mechanism, which implies the obligatory activation of both protein kinases A and C in the transduction of c-fos expression. In summary, this article provides evidence that VIP and PACAP27 potentiate the effect of glutamate, the principal effector on c-fos expression, suggesting that both peptides can increase the "throughput" or "strength" of glutamate-containing circuits in the cerebral cortex.
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PMID:Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide potentiate c-fos expression induced by glutamate in cultured cortical neurons. 779 Aug 51

A consensus AP-1 site in the promoter of the rat neurotensin/neuromedin N (NT/N) gene is a critical regulatory element required for synergistic regulation by combinations of nerve growth factor (NGF), lithium, glucocorticoids, and adenylate cyclase activators. A rapid RNase protection assay was developed to examine the kinetics of NT/N gene activation and to determine whether activation requires newly synthesized proteins. Either NGF or lithium in combination with dexamethasone and forskolin transiently activated NT/N gene expression, but with distinct kinetics. Protein synthesis was not required for activation when NGF was used as the permissive inducer, but was required for the rapid down-regulation of the response. In contrast, lithium responses were attenuated in the absence of protein synthesis, consistent with a requirement for newly synthesized AP-1 complexes in activation. In all cases, increases in NT/N gene expression closely paralleled increases in AP-1 binding activity. Lithium in combination with other inducers caused delayed increases in both AP-1 binding activity and c-jun, c-fos and fra-1 gene expression. These results indicate that NGF and lithium exert their effects on NT/N gene expression through distinct pathways. The lithium pathway is active in neuronally-differentiated PC12 cells and could potentially be involved in the regulation of NT/N gene expression in the nervous system.
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PMID:Synergistic induction of neurotensin gene transcription in PC12 cells parallels changes in AP-1 activity. 789 6

Promoter regions of the preproenkephalin, preprodynorphin, and c-fos genes contain cyclase response elements (CREs) as well as AP-1 sites. Activation of the adenylate cyclase cascade leads to phosphorylation of cyclase response element binding proteins (P-CREBs) which then bind CREs in these genes and induce transcription. In this experiment, semi-quantitative immunocytochemistry was used to examine striatal CREB-, P-CREB-, and Fos-like immunoreactivity (IR) 1 h following intracerebroventricular injection of H2O-soluble forskolin. Although forskolin did not alter CREB-IR, forskolin did induce striatal P-CREB-IR and Fos-IR by 2.5- and 10-fold, respectively. These data support a role for P-CREB and/or Fos in regulating opioid peptide gene transcription following direct in vivo activation of adenylate cyclase.
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PMID:Forskolin increases phosphorylated-CREB and fos immunoreactivity in rat striatum. 791 67

Destruction of the substantia nigra produces striatal D1 dopamine receptor supersensitivity without increasing receptor number or affinity, thus implicating postreceptor mechanisms. The nature of these mechanisms is unknown. Increased striatal c-fos expression ipsilateral to a unilateral lesion of the substantia nigra in rats treated with appropriate dopamine agonists provides a cellular marker of D1 receptor supersensitivity. D1 receptors are positively linked to adenylate cyclase and therefore to cAMP-dependent protein kinase. Because expression of the c-fos gene in response to cAMP- and Ca2+/calmodulin-regulated protein kinases depends on phosphorylation of cAMP-response element-binding protein (CREB) at Ser-133, we examined CREB phosphorylation after dopaminergic stimulation in cultured striatal neurons and in the striatum of rats after unilateral 6-hydroxydopamine ablation of the substantia nigra. Using an antiserum specific for CREB phosphorylated at Ser-133, we found that dopamine increases CREB phosphorylation in cultured striatal neurons. This effect was blocked by a D1 antagonist. L-Dopa produced marked CREB phosphorylation in striatal neurons in rats ipsilateral, but not contralateral, to a 6-hydroxydopamine lesion. This response was blocked by a D1 antagonist, but not a D2 antagonist, and was reproduced by a D1 agonist, but not a D2 agonist. These findings are consistent with the hypothesis that D1 receptor supersensitivity is associated with upregulated activity of cAMP-dependent or Ca2+/calmodulin-dependent protein kinases, or both, following dopamine denervation of striatal neurons.
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PMID:6-Hydroxydopamine lesions of rat substantia nigra up-regulate dopamine-induced phosphorylation of the cAMP-response element-binding protein in striatal neurons. 793 19

In adulthood, thyroid hormone regulates beta adrenergic responsiveness. We addressed whether similar processes operate in the developing brain, thus playing a role in neurotransmitter control of target cell differentiation. Rats were made hyperthyroid [triiodothyronine (T3)] or hypothyroid [propylthiouracil (PTU)] during the immediate perinatal period, and the development of beta adrenergic signal transduction was evaluated in three brain regions. PTU treatment resulted in an ubiquitous deficit in the number of beta receptor binding sites. Although beta adrenergic stimulation of adenylate cyclase activity was also obtunded by PTU, the effects were much less prominent and were restricted to one region (forebrain); comparison with basal adenylate cyclase and with total enzymatic activity (forskolin stimulation) indicated that the differences in isoproterenol response were at the level of adenylate cyclase expression, rather than in specific receptor coupling. PTU also reduced responsiveness of ornithine decarboxylase (ODC), a key enzyme that couples receptors to differentiation, again, changes in receptor-mediated responsiveness reflected alterations in total enzyme activity, rather than effects on receptor coupling. In contrast, measurements of c-fos, a protooncogene that couples cyclic AMP to induction of ODC, showed increased responses to beta adrenergic or cyclic AMP stimulation in PTU-treated animals. The effect of PTU on c-fos responsiveness occurred in the absence of alterations in basal c-fos expression, a situation different from that seen with adenylate cyclase or ODC. T3 administration had only small effects on any of these variables. The role of thyroid hormones thus involves targeting of beta receptors and receptor-mediated stimulation of nuclear transcription factors (c-fos), as well as basal expression of transduction components in the signalling cascade (adenylate cyclase, ODC). The effects of PTU, contrasted with the failure of T3 to enhance development of beta receptors or their transduction components, suggest that thyroid hormone is obligatory for normal development of this pathway, but that endogenous hormone levels are already optimally permissive.
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PMID:Role of thyroid status in the ontogeny of adrenergic cell signaling in rat brain: beta receptors, adenylate cyclase, ornithine decarboxylase and c-fos protooncogene expression. 796 48

The transcription control region of the proto-oncogene c-fos contains multiple cis-acting elements to which specific trans-acting factors bind. One such well-studied binding motif in the c-fos promoter is the major cyclic AMP response element (CRE) TGACGT located at -62/-57. In this study we investigated the role of this element in gene regulation by beta 2-adrenergic/adenylate cyclase signalling and DNA methylation. By transient gene expression assays we were able to show that the c-fos regulatory sequences spanning nucleotides -361 to +13 could mediate gene expression by the beta 2-adrenergic agonist isoproterenol and the phosphodiesterase inhibitor theophylline. For isoproterenol however, a stimulating effect was observed in serum-starved cells, while an inhibitory effect was measured in cells supplemented with serum. The gene regulation by the cAMP elevating agents could be due, at least partially, to the major CRE since this isolated motif mediated gene expression by these drugs. Distinct protein-DNA complexes were obtained with nuclear extracts prepared from cells exposed to isoproterenol or/and theophylline under different serum conditions. We further show that DNA methylation of this CRE may also be involved in gene regulation as methylation of the CRE motif strongly reduced the binding of nuclear proteins.
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PMID:The c-fos cAMP-response element: regulation of gene expression by a beta 2-adrenergic agonist, serum and DNA methylation. 809 31

bFGF is a neurotrophic protein expressed in various regions of the adult peripheral and central nervous system. The present study was undertaken to examine the role of bFGF in multihormonal, catecholaminergic and enkephalinergic cells of the adrenal medulla (AM). Western blot analysis revealed the presence of at least three bFGF isoforms (18, 22/23, and 24 kDa) in cultured bovine AM cells. Incubation of AM cells with the exogenous 18 kDa bFGF produced time-dependent increases in tyrosine hydroxylase (TH) and proenkephalin (PEK) mRNA, with maximal changes occurring at 12 h (TH) or 24 h (PEK) of bFGF exposure. Effects of bFGF on TH and PEK mRNA were non-additive with increases induced by exposure of AM cells to nicotine, the depolarizing agent veratridine, or the adenylate cyclase activator forskolin. These data indicate that bFGF effects may occur through intracellular pathways accessed during transsynaptic induction of TH and PEK genes. The increases in PEK mRNA induced by nicotine or bFGF were inhibited by the calcium antagonist TMB-8. TMB-8 also inhibited bFGF-induced increases in TH mRNA as well. However, treatment with TMB-8 increased basal levels of TH mRNA. The addition of bFGF increased endogenous levels of c-fos mRNA, c-Fos and c-Fos-related proteins, suggesting that bFGF may activate TH and PEK gene expression through a calcium-AP1 transcriptional regulatory pathway. Immunohistochemical analysis revealed the presence of bFGF-immunoreactivity (bFGF-IR) in the cytoplasm and in the nucleus of AM cells. Incubation of cells with exogenous bFGF produced time-dependent increases of nuclear bFGF-IR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Basic fibroblast growth factor (bFGF) regulates tyrosine hydroxylase and proenkephalin mRNA levels in adrenal chromaffin cells. 810 Jan 72

As major signal transduction cascades, the protein kinase-A and -C (PKA and PKC) pathways have been implicated in the regulation of GnRH synthesis and secretion in the hypothalamus. We have investigated the roles of these pathways in the regulation of GnRH transcription, mRNA levels, propeptide processing, and secretion in GT1-7 cells, a mouse hypothalamic GnRH neuronal cell line. Forskolin, which activates adenylate cyclase to raise cAMP levels, had no effect on GnRH mRNA levels at 10 microM, but induced c-fos mRNA at 30 min. An activator of PKC, 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 nM), also induced c-fos at 30 min, but produced a progressive decline in GnRH mRNA, resulting in a 70% decrease by 16 h. Coadministration of 10 nM TPA and 20 microM of a PKC inhibitor, NPC 15437 [2,6-diamino-N-([1-(1-oxotridecyl)2-piperidinyl]methyl)hexanami de], prevented c-fos induction, but did not antagonize GnRH repression. Instead, the inhibitor itself reduced GnRH mRNA levels by 56% at 16 h (with no effect on c-fos mRNA). Thus, since extended exposure to TPA can down-regulate PKC, suppression of GnRH mRNA by TPA may be due to decreased PKC activity, indicating a role for PKC in the maintenance of the GnRH gene expression (a role that is unlikely to involve c-fos). In transient transfections, the transcriptional activity from 3 kilobases of GnRH 5'-flanking sequence was repressed 2-fold by either 100 nM TPA or 20 microM NPC 15437 at 24 h, demonstrating that suppression of GnRH mRNA is at least, in part, at the level of transcription. In contrast, both TPA (100 nM) and forskolin (10 microM) stimulated secretion. Enhancement of GnRH secretion by TPA was robust and rapid (2.5 min), while the response to forskolin was relatively delayed (2 h). Over a 24-h period, unstimulated cells released primarily unprocessed prohormone, whereas forskolin and TPA stimulated the secretion of processed products. These data indicate that PKC and PKA may influence propeptide processing and/or the route of GnRH secretion. These data demonstrate that the PKA and PKC pathways regulate GnRH at the multiple levels of transcription, pro-GnRH processing, and GnRH secretion.
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PMID:Regulation of gonadotropin-releasing hormone by protein kinase-A and -C in immortalized hypothalamic neurons. 850 41

Microglia, like other tissue macrophages, are a component of the hypothalamic-pituitary endocrine-immune axis and, as such, are responsive to both neural and endocrine factors. Using cultured neonatal hamster microglia, we have examined the effect of isoproterenol, a beta-adrenergic agonist, and dexamethasone, a synthetic glucocorticoid, on superoxide anion production. For these experiments, microglia were pretreated with isoproterenol or dexamethasone and then induced to produce superoxide anion by exposure of the cells to phorbol myristate acetate (PMA). Our study demonstrates that the PMA-stimulated production of superoxide anion was decreased by acute (30 min) and chronic (24 h) pretreatment of the microglia with isoproterenol and was blocked by the beta-adrenergic receptor antagonist, propranolol. Since a rise in intracellular cAMP may be a prime factor in the inhibition of superoxide anion production in isoproterenol-treated cells, we used forskolin, a known activator of the adenylate cyclase in place of isoproterenol and re-investigate superoxide anion production. Short term exposures to forskolin produced a lower amount of superoxide anion than PMA-stimulated alone and, thus, mimicked the effect of isoproterenol. However, treatment with the same concentration of forskolin for 24 h prior to the induction of the NADPH oxidase did not significantly change PMA-stimulated superoxide anion production from untreated values. Thus, chronic exposure to forskolin produced a different effect than chronic exposure to isoproterenol. Isoproterenol and forskolin both increased immunoreactivity for the protein products of the early response genes, c-fos and c-jun. Pretreatment with dexamethasone for 24 h also inhibited superoxide anion production and was blocked by the protein synthesis inhibitor, cycloheximide. The simultaneous addition of varying concentrations of dexamethasone and 5 microM isoproterenol did not produce a greater inhibition in superoxide anion production than either agent alone. The down-regulation of microglial function by adrenergic agonists and by glucocorticoids provides a way in which the cytotoxicity of these immune cells can be reduced and may be a factor in the paracrine regulation of microglia.
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PMID:Inhibition of microglial superoxide anion production by isoproterenol and dexamethasone. 880 88


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