Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By northern blot analysis and ribonuclease protection assay, we observed the presence of a high level of trkB mRNA in primary brain cultures devoid of neuronal cells and highly enriched in glial fibrillary acidic protein-positive astroglial cells prepared from newborn rat cerebral hemispheres, cerebral cortex, hippocampus, and striatum. In primary astroglial cultures, the more abundant trkB transcripts code for the truncated receptor without tyrosine kinase activity; probes specific for the full-length trkB mRNA did not detect any signal in northern blot analysis. By the sensitive ribonuclease protection assay, we could show the presence of trkC mRNA in cultured astrocytes, whereas no trkA mRNA was detected. We confirmed the presence of relatively high levels of nerve growth factor and neurotrophin-3 mRNA, and very low basal level of brain-derived neurotrophic factor mRNA. Moreover, we demonstrated that another member of the neurotrophin family, neurotrophin-4, is also expressed in cultured astroglial cells. In view of the fact that many functional receptors for conventional neurotransmitters or neuropeptides present on astroglial cells may act via the adenylate cyclase system, we studied also the effect of agents able to increase the intracellular cyclic AMP concentration. A sharp increase in the trkB mRNA level was observed after treatment of primary astroglial cultures with dibutyryl cyclic AMP, 8-bromo-cyclic AMP, or the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine. On the contrary, trkC mRNA levels were unaffected by treatment with cyclic AMP-elevating agents. All the neurotrophin mRNAs examined, except neutrophin-4, were increased by 3-isobutyl-1-methylxanthine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of neurotrophins and their receptors in primary astroglial cultures: induction by cyclic AMP-elevating agents. 751 99

We have shown previously that a soluble factor(s) released by the myenteric plexus promotes neurite outgrowth from postnatal striatal neurons, and that this effect was abolished by tetrodotoxin. We have now investigated the possible involvement of purines in the mediation of this neuritogenic response, by examining their effect on neurite length of striatal neurons both in co-culture with myenteric plexus explants and cultured alone. Both ATP and 2-chloroadenosine partially reversed the inhibitory effect of tetrodotoxin in co-cultures with whole myenteric plexus, while the stable ATP analogue, alpha, beta-methylene ATP, had no effect, suggesting that ATP was being broken down to adenosine before exerting its action. Further support for this view was that the ATP (P2) purinoceptor antagonist suramin did not reverse the effects of ATP, while the adenosine (P1) purinoceptor antagonist 8-(p-sulphophenyl)theophylline did antagonize the effects of ATP in tetrodotoxin-treated co-cultures. Further, both 8-(p-sulphophenyl)theophylline and adenosine deaminase reduced the effect of the myenteric plexus on striatal neurons in the absence of tetrodotoxin, and the adenylate cyclase activator forskolin completely reversed the effect of tetrodotoxin in our co-culture system. The neurite outgrowth-promoting effect of 2-chloroadenosine in tetrodotoxin-treated co-cultures was not further enhanced by a combination of neuropeptides. Serotonin and GTP were without effect on striatal neurons in the presence or absence of myenteric plexus explants. In experiments without myenteric plexus, both 2-chloroadenosine and forskolin caused a slight increase in striatal neurite length; ATP and GTP were ineffective. Basic fibroblast growth factor, nerve growth factor, neurotrophin-3 or neurotrophin-4/5 had no effect on neurite outgrowth in postnatal striatal cultures after two days in vitro. When these growth factors were added in combination with 2-chloroadenosine, the observed increase in mean neurite length did not exceed that induced by 2-chloroadenosine alone. Both 2-chloroadenosine and the ganglioside mix AGF1 increased neurite elongation of striatal neurons after two days in vitro, but an inhibition of enhanced neurite outgrowth was observed when both substances were added together. Both laminin and fibronectin were not neuritogenic for postnatal striatal neurons under our culture conditions. These observations suggest that a factor other than the growth factors tested here is involved in the promotion of striatal neurite outgrowth in co-culture with myenteric plexus explants. In summary, adenosine (probably acting through the A2 subclass of the P1 purinoceptor) leads to increased striatal neurite outgrowth in co-culture with myenteric plexus and we propose that it does so either (1) by triggering the release of a neuritogenic factor, possibly from enteric glial cells, or (2) by acting synergistically with such a growth factor. Adenosine acts via P1 purinoceptors, which leads to changes in cyclic AMP, and the response to forskolin suggests that cyclic AMP is probably involved in the events leading to increased striatal neurite outgrowth.
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PMID:Neurite outgrowth of striatal neurons in vitro: involvement of purines in the growth-promoting effect of myenteric plexus explants. 888 77

The aim of the study was to determine which factors regulated the expression of neurotrophin-3 (NT-3) mRNA in cultured primary Schwann cells derived from sciatic nerve of neonatal rats. Treatment of primary Schwann cells with the adenylate cyclase activator, forskolin, or the cAMP agonist, 8-Br-cAMP, induced a significant reduction in NT-3 transcript levels. Transforming growth factor-beta1 (TGF-beta1) and glial growth factor 2 (GGF(2)) also reduced the levels of NT-3 mRNA in a dose and time-dependent manner. Treatment with nerve growth factor, brain-derived neurotrophic factor, NT-3, ciliary neurotrophic factor or interleukin-1beta was without effect. The TGF-beta1, GGF(2) and forskolin dependent reduction in NT-3 mRNA levels involved a destabilization of transcripts which was antagonised by co-treatment with cycloheximide. The cAMP-dependent protein kinase A (PKA) inhibitor, H-89, blocked the reduction in levels of NT-3 mRNA induced by TGF-beta1, GGF(2) and forskolin. The data show that the effects of TGF-beta1, GGF(2) and forskolin on the downregulation of NT-3 mRNA, at least in part, were due to a post-transcriptional event involving a labile protein intermediate under the control of PKA. The results suggest that the down-regulation of NT-3 mRNA in Schwann cells at a site of peripheral nerve damage may be mediated via a cAMP-dependent pathway and possibly involve neuroma-related elevations in TGF-beta1 and GGF(2).
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PMID:Transforming growth factor-beta1 and glial growth factor 2 reduce neurotrophin-3 mRNA expression in cultured Schwann cells via a cAMP-dependent pathway. 1052 80