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)

Brain-derived neurotrophic factor (BDNF) and NGF are both expressed by neurons in the hippocampus. In previous studies, it has been demonstrated that both BDNF and NGF mRNA levels are regulated by neuronal activity. Upregulation is predominantly regulated by the glutamate (NMDA and non-NMDA receptors); downregulation, predominantly by the GABA system (Zafra et al., 1990, 1991). In neuronal cultures of the rat hippocampus, potassium depolarization and kainic acid-mediated increases in BDNF and NGF mRNA were eliminated in a dose-dependent manner by the calcium channel blocker nifedipine. Conversely, calcium ionophores (Bay-K8644 and ionomycin) augmented BDNF and NGF mRNA levels by a calmodulin-mediated mechanism. In view of the fact that many potential modulators (conventional transmitters and neuropeptides) of neuronal and astrocytic BDNF and NGF mRNA synthesis may act via the adenylate cyclase system, we studied the effect of forskolin, an activator of adenylate cyclase. Indeed, forskolin enhanced the effects of calcium ionophores and kainic acid on BDNF and NGF mRNA levels. Cytokines, such as interleukin-1 and transforming growth factor-beta 1, which have previously been shown to increase NGF mRNA markedly in astrocytes, were without effect on neuronal BDNF and NGF mRNA levels. In contrast to neuronal cultures, where the regulation of BDNF and NGF mRNA was generally very similar, the regulation in astrocytes was distinctly different. All the cytokines that produce a marked increase in NGF mRNA were without effect on astrocyte BDNF mRNA levels, which under basic conditions were below the detection limit. However, norepinephrine produced a marked elevation of BDNF mRNA in astrocytes, an effect that was further enhanced by glutamate receptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of brain-derived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes. 128 95

Hormone and neutrotransmitter receptor systems regulate both the activity and expression of GTP-binding proteins (G-proteins). However, relatively little is known about the mechanism by which this regulation occurs. One G-protein subtype, Gi alpha 1, is expressed primarily in neuronal cells. Here, we demonstrate the selective regulation of Gi alpha 1 mRNA and protein levels by cAMP. Treatment of PC12 cells with forskolin increases Gi alpha protein levels. Similarly, incubation of PC12 cells with agents that increase intracellular levels of cAMP, including forskolin, dibutyryl-cAMP, and 8-bromo-cAMP, induce a two- to fourfold increase in Gi alpha 1 mRNA levels. Furthermore, the effect of increased intracellular cAMP is specific for Gi alpha 1 mRNA expression; the levels of mRNA encoding other G-protein subtypes remain unaltered. cAMP-stimulated Gi alpha 1 expression occurs within hours of treatment and is sustained for days. Increasing intracellular cAMP by activation of cell surface adenosine receptors also increases Gi alpha 1 mRNA levels. Treatment of PC12 cells with phorbol esters, NGF, or depolarizing concentrations of KCl did not increase Gi alpha 1 mRNA expression, demonstrating that Gi alpha 1 expression is specifically regulated by cAMP. Guanine nucleotide-mediated inhibition of adenylate cyclase activity was measured in order to determine if the change in Gi alpha protein expression was accompanied by a change in G-protein function. Adenylate cyclase activity in PC12 cells treated with an adenosine analog and therefore expressing higher levels of Gi alpha protein is more sensitive to inhibition by guanine nucleotides than in nontreated PC12 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective regulation of Gi alpha 1 expression and function in PC12 cells by cAMP. 131 51

We have previously shown that after peripheral nerve lesion the synthesis of NGF is induced in cells of the nerve sheath (Heumann et al., 1987a). Further analysis led to the identification of growth factors and intracellular mechanisms responsible for this induction in sciatic fibroblasts (Lindholm et al., 1988; Hengerer et al., 1990). The present work aimed at the elucidation of the regulation of NGF synthesis in Schwann cells. A variety of cytokines and peptide growth factors, including interleukin-1 (IL-1) and platelet-derived growth factor (PDGF), which are known to increase NGF-mRNA in fibroblasts and astrocytes, failed to do so in Schwann cell cultures. Forskolin (FK), an activator of adenylate cyclase, increased the level of NGF-mRNA eightfold within 3 hr of incubation. The effect of FK on NGF-mRNA was mimicked by analogs of cAMP but not by dideoxyforskolin, an FK derivative not activating adenylate cyclase. Application of norepinephrine and isoproterenol also augmented the NGF-mRNA content. Pretreatment of Schwann cells with N-[2-(methylamino)ethyl]-5-isoquinoline sulfonamide dihydrochloride (H-8), an inhibitor of cyclic-nucleotide-dependent protein kinases, decreased both basal and elevated levels of NGF-mRNA. Ionomycin, a Ca2+ ionophore, and phorbol 12-myristate 13-acetate (TPA), an activator of protein kinase C, potentiated the effect of FK in an H-8-sensitive manner. We show that the action of FK is independent of changes in mRNA stability and of protein synthesis. Thus, in cultured Schwann cells upregulation of NGF-mRNA expression seems to be mainly achieved by a cAMP-triggered transcriptional activation of the NGF gene. Another striking difference between various glial cell types was revealed by application of transforming growth factor beta-1 (TGF-beta 1), which is the strongest inducer of NGF-mRNA in cultured astrocytes (Lindholm et al., 1990). Schwann cells responded to TGF-beta 1 by decreasing basal as well as FK-induced NGF-mRNA levels. Together with previously published work, our results show that cell-type-specific mechanisms not only account for the different control of NGF expression in neurons as compared to glial cells, but also reveal a surprising specificity of regulatory mechanisms in different non-neuronal cell types, even those derived from the same tissue such as fibroblasts and Schwann cells of peripheral nerves.
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PMID:Cell-type-specific regulation of nerve growth factor (NGF) synthesis in non-neuronal cells: comparison of Schwann cells with other cell types. 165 45

The expression of the gene encoding the neuroendocrine peptides neurotensin (NT) and neuromedin N is strictly dependent on simultaneous exposure to multiple inducers in PC12 pheochromocytoma cells. NT peptide and NT/N mRNA levels are synergistically induced by combinations of NGF, dexamethasone, activators of adenylate cyclase, and lithium ion. We have used transient transfection assays to delineate the rat NT/N gene sequences necessary for this complex regulation. Progressive deletions of the 5' flanking region revealed that sequences between -216 and +56 are sufficient to confer the full spectrum of responses exhibited by the endogenous gene to a reporter gene. Detailed mutational analysis of this region indicates that it is composed of an array of inducible cis-regulatory sequences, including AP-1, cAMP response, and glucocorticoid response elements. Specific mutation of either the AP-1 site or each of two cAMP response elements indicates that they are functionally interdependent. This array of response elements serves to integrate multiple environmental stimuli into a unified transcriptional response.
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PMID:Mutually dependent response elements in the cis-regulatory region of the neurotensin/neuromedin N gene integrate environmental stimuli in PC12 cells. 234 11

The effect of NGF from bovine seminal plasma on the adenylate cyclase system of pheochromocytoma PC12 cell line was studied. It was shown that the elevation of the intracellular level of cAMP caused the NGF-like morphological differentiation of PC12 cells cultured in the serum-free medium. This effect was very transitory because of the compensatory action of phosphodiesterase of cAMP, the biosynthesis of which was induced by the elevated level of intracellular cAMP. Inhibition of the adenylate cyclase activity in the membrane preparation of PC12 cells was observed. This inhibition can be a result of a decrease in the level of endogenous ADP-ribosylation which was detected after incubation of cells with NGF. The parameters of this process were investigated. It was demonstrated that morphological differentiation of PC12 cells can be induced by serotonin (neurotransmitter), L-carnosine (dipeptide) and retinoic acid (vitamin A derivative). The possible mechanisms of action of these substances were suggested. It was shown that serotonin inhibited adenylate cyclase of PC12 cells, whereas the combined action of NGF and serotonin led to the activation of the enzyme. The hypothetic mechanism of this process was proposed.
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PMID:Regulation of differentiation of PC12 cells by nerve growth factor. 285 51

Low concentrations (10-50 microM) of adenosine (EC50 = 17 microM) or chloroadenosine (EC50 = 23 microM) prevent the division of PC12 cells. This inhibition is not mimicked by guanosine, inosine, 3',5' dideoxyadenosine, phenylisopropyladenosine, or adenylylimidodiphosphate. The growth inhibition is not relieved by addition of uridine or deoxycytidine, nor is it potentiated by homocysteine thiolactone. Inhibition of adenosine uptake does not inhibit adenosine-dependent growth arrest. PC12 variants that are deficient in adenosine kinase are as sensitive as wild-type cells to the growth-inhibitory effects of adenosine. These experiments suggest that adenosine prevents cell division at an adenosine receptor rather than acting after being metabolically altered. The adenosine receptor that inhibits cell division does not appear to be the adenosine receptor that stimulates adenylate cyclase for these reasons: (1) phenylisopropyladenosine, which is a potent agonist of this receptor, does not inhibit cell division; (2) 3',5' dideoxyadenosine does not antagonize the effect of adenosine on cell division; and (3) theophylline does not affect growth inhibition by adenosine. Thus, these experiments suggest the existence of a second adenosine receptor that can inhibit cell division. Adenosine also promotes the morphological differentiation of PC12 cells. In the presence of the adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenosine (EHNA), adenosine causes the formation of short neurites (one-half to one and one-half cell diameters in length). Adenosine also increases the rate of neurite formation of both long and short neurites in response to NGF.
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PMID:Adenosine inhibits cell division and promotes neurite extension in PC12 cells. 608 75

Adult rat chromaffin cells proliferate in vivo in response to neurally derived signals. Their proliferation in vitro is stimulated either by peptide growth factors or by activators of adenylate cyclase or protein kinase C that mimic the effects of neurotransmitters in adrenal medullary nerve endings. Differing susceptibilities to inhibitors and potentiators suggest that growth factors, cyclic AMP-dependent protein kinases and protein kinase C act via partially distinct and partially overlapping signalling pathways. Depolarization inhibits the mitogenic response to NGF, through a mechanism that apparently involves activation of voltage-gated calcium channels, while sparing the response to phorbol esters that activate PKC. Activators of adenylate cyclase also inhibit the response to NGF. The findings suggest that during normal development, neurally derived signals supersede growth factors in regulating proliferation of chromaffin cells by selectively inhibiting or co-opting portions of growth factor signalling pathways. This model might be generally applicable to the development of the nervous system.
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PMID:Multiple mitogenic signalling pathways in chromaffin cells: a model for cell cycle regulation in the nervous system. 751 60

Adult rat chromaffin cells in vitro show a large proliferative response to NGF, followed by neuronal differentiation. Infection of replicating chromaffin cells with a retrovirus carrying the Escherichia coli beta-galactosidase (beta-gal) gene demonstrates beta-gal expression in cells that continue to multiply, that differentiate into neurons, and that become static. The effects of NGF on proliferation and differentiation are abolished by the protein kinase inhibitors K252a and staurosporine, and by cholera toxin, an activator of adenylate cyclase. They are diminished, but not abolished, by high concentrations of dexamethasone. Both cholera toxin alone and phorbol myristate acetate (PMA), an activator of protein kinase C, elicit small and inconsistent mitogenic responses. The responses to PMA cannot be shown to be additive with the effects of NGF. NGF is a known mitogen and neuritogen for chromaffin cells from neonatal rats, but has not previously been believed to affect similarly chromaffin cells from adults. The present findings suggest that portions of NGF signaling pathways might continue to be involved in regulating proliferation of adult rat chromaffin cells in vivo, and might be constitutively activated in PC12 cells and other adrenal medullary tumors. They further suggest that rat chromaffin cells might be propagated in vitro to obtain large numbers of sympathetic neurons expressing normal or exogenous genes.
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PMID:Nerve growth factor is a potent inducer of proliferation and neuronal differentiation for adult rat chromaffin cells in vitro. 846 33

We have previously shown that N(6)-methyldeoxyadenosine (MDA) is an inducer of differentiation in several tumor cells. Here we show that in addition to its ability to induce neurite-outgrowth in PC12 cells, MDA also significantly enhances the nerve-growth factor-mediated neurite outgrowth of these cells. Thus, MDA acts synergistically with NGF to repress cdc2 and cdk2 synthesis and to enhance tyrosine hydroxylase synthesis. To further elucidate the mechanisms of action of MDA, we investigated the effect of this drug on various signaling pathways. The neuritogenesis observed in PC12 following MDA treatment is mediated through activation of adenylyl cyclase in a PKA independent process and through the recruitment of the p44/p42 MAPK pathway. Furthermore, the adenosine A(2a) receptor antagonist ZM 241385 prevents the MDA-induced neuritogenesis, suggesting that MDA mediates its effect via this adenylyl cyclase-coupled A(2a) receptor. Collectively, these findings suggest that, in PC12 cells, the MDA-induced neuritogenesis requires the recruitment of adenosine A(2a) receptor, the stimulation of adenylate cyclase, and the activation of the p44/42MAP kinase cascade.
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PMID:Induction of neurite outgrowth in PC12 cells by the bacterial nucleoside N6-methyldeoxyadenosine is mediated through adenosine A2a receptors and via cAMP and MAPK signaling pathways. 1272 27

Developing neurons encounter a panoply of extracellular signals as they differentiate. A major goal is to identify these extrinsic cues and define the mechanisms by which neurons simultaneously integrate stimulation by multiple factors yet initiate one specific biological response. Factors that are known to exert potent activities in the developing nervous system include the NGF family of neurotrophic factors, ciliary neurotrophic factor (CNTF), and pituitary adenylate cyclase-activating peptide (PACAP). Here we demonstrate that PACAP promotes the differentiation of nascent dorsal root ganglion (DRG) neurons in that it increases both the number of neural-marker-positive cells and axonogenesis without affecting the proliferation of neural progenitor cells. This response is mediated through the PAC1 receptor and requires MAP kinase activation. Moreover, we find that, in the absence of exogenously added PACAP, blockade of the PAC1 receptor inhibits neuronal differentiation. These data coupled with our finding that both PACAP and the PAC1 receptor are expressed during the peak period of neuronal differentiation in the DRG suggest that PACAP functions in vivo to promote the differentiation of nascent sensory neurons. Interestingly, we also demonstrate that the neurotrophic factors NT-3 and CNTF completely block the PACAP-induced neuronal differentiation. This points to the intricate integration of cellular signals by nascent neurons and, to our knowledge, is the first evidence for neurotrophic factor abrogation of a pathway regulated by G-protein-coupled receptors (GPCRs).
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PMID:PACAP promotes sensory neuron differentiation: blockade by neurotrophic factors. 1508 Aug 92


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