Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurotrophins are a family of soluble ligands that promote the survival and differentiation of peripheral and central neurons and regulate synaptic function. The two neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), bind and activate a single high-affinity receptor, TrkB. Experiments in cell culture have revealed that an intact Shc adaptor binding site on TrkB and subsequent activation of the Ras/MAPK pathway are important for neuronal survival and neurite outgrowth. To elucidate the intracellular signaling pathways that mediate the diverse effects of BDNF and NT4 in vivo, we have mutated in the mouse germline the Shc binding site in the trkB gene. This trkB(shc) mutation revealed distinctive responses to BDNF and NT4. While nearly all NT4-dependent sensory neurons were lost in trkB(shc/shc) mutant mice, BDNF-dependent neurons were only modestly affected. Activation of MAP kinases and in vitro survival of cultured trkB(shc/shc) neurons were reduced in response to both neurotrophins, with NT4 being less potent than BDNF, suggesting differential activation of TrkB by the two ligands. Moreover, while the Ras/MAPK pathway is required for in vitro differentiation of neuronal cells, trkB(shc/shc) mutant mice do not show any defects in BDNF-dependent differentiation of CNS neurons or in the function of sensory neurons that mediate innocuous touch.
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PMID:Point mutation in trkB causes loss of NT4-dependent neurons without major effects on diverse BDNF responses. 972 15

Neurotrophins exert short- and long-term effects on synaptic transmission. The mechanism underlying these forms of synaptic plasticity is unknown although it is likely that intracellular Ca2+ and presynaptic Ca2+ channels play a critical role. Here we show that BDNF, NGF and NT-3 (10-100 ng/mL) exhibit a selective long-term up-regulation of voltage-gated Ca2+ current densities in developing hippocampal neurons of 6-20 days in culture. NGF and NT-3 appear more effective in up-regulating L-currents, while BDNF predominantly acts on non-L-currents (N, P/Q and R). The effects of the three neurotrophins were time- and dose-dependent. The EC50 was comparable for BDNF, NGF and NT-3 (10-16 ng/mL) while the time of half-maximal activation was significantly longer for NGF compared to BDNF (58 vs. 25 h). Despite the increased Ca2+ current density, the neurotrophins did not alter the voltage-dependence of channel activation, the kinetics parameters or the elementary properties of Ca2+ channels (single-channel conductance, probability of opening and mean open time). Neurotrophin effects were completely abolished by coincubation with the nonspecific Trk-receptor inhibitor K252a, the protein synthesis blocker anisomycin and the MAP-kinase inhibitor PD98059, while cotreatment with the PLC-gamma blocker, U73122, was without effect. Immunocytochemistry and Western blotting revealed that neurotrophins induced an increased MAP-kinase phosphorylation and its translocation to the nucleus. The present findings suggest that on a long time scale different neurotrophins can selectively up-regulate different Ca2+ channels. The action is mediated by Trk-receptors/MAP-kinase pathways and induces an increased density of newly available Ca2+ channels with unaltered gating activity.
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PMID:BDNF, NT-3 and NGF induce distinct new Ca2+ channel synthesis in developing hippocampal neurons. 1106 98

Although mood disorders have traditionally been regarded as good prognosis diseases, a growing body of data suggests that the long-term outcome for many patients is often much less favorable than previously thought. Recent morphometric studies have been investigating potential structural brain changes in mood disorders, and there is now evidence from a variety of sources demonstrating significant reductions in regional CNS volume, as well as regional reductions in the numbers and/or sizes of glia and neurons. Furthermore, results from recent clinical and preclinical studies investigating the molecular and cellular targets of mood stabilizers and antidepressants suggest that a reconceptualization about the pathophysiology and optimal long-term treatment of recurrent mood disorders may be warranted. It is proposed that impairments of neuroplasticity and cellular resilience may underlie the pathophysiology of mood disorders, and further that optimal long-term treatment for these severe illnesses may only be achieved by the early and aggressive use of agents with neurotrophic/neuroprotective effects. It is noteworthy that lithium, valproate and antidepressants indirectly regulate a number of factors involved in cell survival pathways including CREB, BDNF, bcl-2 and MAP kinases, and may thus bring about some of their delayed long-term beneficial effects via underappreciated neurotrophic effects. The development of novel treatments which more directly target molecules involved in critical CNS cell survival and cell death pathways have the potential to enhance neuroplasticity and cellular resilience, and thereby modulate the long-term course and trajectory of these devastating illnesses.
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PMID:Neuroplasticity and cellular resilience in mood disorders. 1112 89

We report that the Forkhead family of transcription factors, FKHRL1, FKHR and AFX are novel components of neurotrophin receptor signaling. NGF rapidly induced the phosphorylation of FKHRL1 in PC12 cells. This effect is mediated by high-affinity TrkA receptor as nerve growth factor (NGF) induced the phosphorylation of FKHRL1 only in TrkA expressing cells and not p75-expressing cells. Additional experiments with various kinase inhibitors, the transient expression of constitutively active and dominant-negative Akt, and in vitro kinase assay revealed that phosphatidylinositol-3 (PtdIns3)/Akt kinase mediated the actions of NGF. Similar data were obtained for brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) in primary cortical cultured neurons. These findings demonstrate for the first time that the phosphorylation of the Forkhead family of transcription factors can be modulated by neurotrophins via Trk receptors and PtdIns3K/Akt kinase (but not MAP or S6p70 kinases) in neuronal and non-neuronal cells. Moreover, survival assays with the PtdIns3 kinase inhibitor LY294002, active and dominant-negative forms of Akt indicate that the phosphorylation of FKHRL1 plays a role in neurotrophins-mediated cell survival.
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PMID:FKHRL1 and its homologs are new targets of nerve growth factor Trk receptor signaling. 1195 55

Neuroprotective actions of scatter factor/hepatocyte growth factor (SF/HGF) have not been described. We examined the effects of SF/HGF in comparison to acidic fibroblast growth factor-1 (FGF-1) on N-methyl-D-aspartate (NMDA) and quinolinic acid (QUIN)-induced excitotoxicity in primary cerebellar granule neurons. Exposure to NMDA or QUIN for 24 h resulted in concentration-dependent cell death (p < 0.001) that was completely attenuated (p < 0.001) by pre-treatment of cells with SF/HGF (50 ng/mL) or FGF-1 (40 ng/mL). SF/ HGF and FGF-1 activated both Akt and MAP-kinase > threefold (p < 0.001). Neither SF/HGF nor FGF-1 activated cyclic AMP-response element binding protein (CREB), a downstream target of MAP-kinase, whereas brain-derived neurotrophic factor (BDNF) activated both MAP-kinase and CREB in granule neurons. Neuroprotection against NMDA or QUIN by SF/HGF and FGF-1 was negated by the addition of LY294002 (10 microM) or wortmannin (100 microM), two distinct inhibitors of phosphatidylinositol 3-kinase (P13-K), but not by the MAP-kinase kinase (MEK) inhibitor PD98059 (33 microm). Likewise, expression of a dominant-negative mutant of Akt (Akt-kd) completely prevented the neuroprotective actions of SF/HGF and FGF-1. Overexpression of a constitutively activated Akt (Akt-myr) or wild-type Akt (wtAkt) attenuated excitotoxic cell death. These data show that both SF/HGF and FGF-1 protect cerebellar granule neurons against excitotoxicity with similar potency in a P13-K/Akt-dependent and MAP-kinase/CREB-independent manner.
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PMID:Neuroprotection by scatter factor/hepatocyte growth factor and FGF-1 in cerebellar granule neurons is phosphatidylinositol 3-kinase/akt-dependent and MAPK/CREB-independent. 1206 84

The TrkB receptor tyrosine kinase and its ligand, BDNF, have an essential role in certain forms of synaptic plasticity. However, the downstream pathways required to mediate these functions are unknown. We have studied mice with a targeted mutation in either the Shc or the phospholipase Cgamma (PLCgamma) docking sites of TrkB (trkB(SHC/SHC) and trkB(PLC/PLC) mice). We found that hippocampal long-term potentiation was impaired in trkB(PLC/PLC) mice, but not trkB(SHC/SHC) mice. BDNF stimulation of primary neurons derived from trkB(PLC/PLC) mice fully retained their ability to activate MAP kinases, whereas induction of CREB and CaMKIV phosphorylation was strongly impaired. The opposite effect was observed in trkB(SHC/SHC) neurons, suggesting that MAPKs and CREB act in parallel pathways. Our results provide genetic evidence that TrkB mediates hippocampal plasticity via recruitment of PLCgamma, and by subsequent phosphorylation of CaMKIV and CREB.
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PMID:Mechanism of TrkB-mediated hippocampal long-term potentiation. 1236 11

Mood disorders have traditionally been conceptualized as neurochemical disorders, but there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes of glia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggests that mood disorders are associated with impairments of structural plasticity and cellular resilience. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell survival and cell death are long-term targets for the actions of antidepressants and mood stabilizers. Antidepressants, lithium, and valproate indirectly regulate a number of factors involved in cell survival pathways, including CREB, BDNF, Bcl-2, and MAP kinases, and may thus bring about some of their delayed long term beneficial effects via underappreciated neurotrophic effects. The future development of treatments that more directly target molecules involved in critical CNS cell survival and cell death pathways thus hold promise as novel, improved long-term treatments for mood disorders.
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PMID:Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. 1239 85

Telomerase, a reverse transcriptase that maintains chromosome ends (telomeres) during successive cell divisions in mitotic cells is present in neuroblasts and early postmitotic embryonic neurons but is absent from adult neurons. The signals that control telomerase levels during development are unknown, as are the functions of telomerase in developing neurons. We now report that telomerase activity and levels of its catalytic subunit telomerase reverse transcriptase (TERT) are increased in embryonic hippocampal neurons by brain-derived neurotrophic factor (BDNF) and a secreted form of beta-amyloid precursor protein (sAPP). BDNF and sAPP promote the survival of the embryonic neurons, and these trophic effects are blocked when TERT production is suppressed using antisense technology. Telomerase is required for the long-term survival of early postmitotic neurons during a time window of approximately 1 week in culture; telomerase is then downregulated and is not required for BDNF and sAPP survival signaling in mature neurons. The increase in telomerase activity and trophic effects of BDNF and sAPP are mediated by phosphatidylinositol-3 kinase and p42/p44 MAP kinases. Our findings demonstrate a requirement for telomerase in the cell survival-promoting actions of BDNF and sAPP in early postmitotic hippocampal neurons, suggesting a previously unknown role for telomerase in mediating the biological actions of neurotrophic factors during brain development.
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PMID:Telomerase mediates the cell survival-promoting actions of brain-derived neurotrophic factor and secreted amyloid precursor protein in developing hippocampal neurons. 1248 64

P19 embryonic carcinoma cells can be differentiated into neurons that form synaptic connections and that produce a variety of neurotransmitters. Results of RT-PCR indicate that P19 neurons express several neurotrophin receptors (p75(NTR), trkB, and trkC, but not trkA) but they do not express any of the four neurotrophins. Consistent with the presence of trkB but not trkA, BDNF causes rapid phosphorylation of MAP kinases ERK1 and ERK2, but NGF does not. Neurotrophins induce translocation of NF-kappaB into the nucleus. All four neurotrophins induce activation of NF-kappaB in a biphasic manner. This effect is apparently mediated by p75(NTR), because an inhibitor of trk receptors, K252a, does not inhibit activation of NF-kappaB. Instead, K252a itself promotes activation of NF-kappaB and this effect is additive with the effect of neurotrophins. Inhibition of reactive oxygen intermediates with PDTC completely abolishes basal activity of NF-kappaB and strongly inhibits activation of NF-kappaB by neurotrophins, indicating an important role of reactive oxygen intermediates in the pathway by which neurotrophins activate NF-kappaB. NF-kappaB is known to promote expression of the iNOS gene. We found that all four neurotrophins increased iNOS mRNA levels, resulting in increased accumulation of iNOS protein. In contrast, none of the neurotrophins stimulated nNOS mRNA or protein synthesis. PDTC abolishes constitutive and neurotrophin-induced expression of iNOS mRNA and protein and abolishes constitutive expression of nNOS mRNA, suggesting that reactive oxygen intermediates promote expression of nNOS.
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PMID:p75 neurotrophin receptor mediates neurotrophin activation of NF-kappa B and induction of iNOS expression in P19 neurons. 1267 17

There is growing evidence from neuroimaging and ostmortem studies that severe mood disorders, which have traditionally been conceptualized as neurochemical disorders, are associated with impairments of structural plasticity and cellular resilience. It is thus noteworthy that recent preclinical studies have shown that critical molecules in neurotrophic signaling cascades (most notably cyclic adenosine monophosphate [cAMP] response element binding protein, brain-derived neurotrophic factor, bcl-2, and mitogen activated protein [MAP] kinases) are long-term targets for antidepressant agents and antidepressant potentiating modalities. This suggests that effective treatments provide both trophic and neurochemical support, which serves to enhance and maintainnormal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. For many refractory patients, drugs mimicking "traditional" strategies, which directly or indirectly alter monoaminergic levels, may be of limited benefit. Newer "plasticity enhancing" strategies that may have utility in the treatment of refractory depression include N-methyl-D-aspartate antagonists, alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA) potentiators, cAMP phosphodiesterase inhibitors, and glucocorticoid receptor antagonists. Small-molecule agents that regulate the activity f growth factors, MAP kinases cascades, and the bcl-2 family of proteins are also promising future avenues. The development of novel, nonaminergic-based therapeutics holds much promise for improved treatment of severe, refractory mood disorders.
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PMID:Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. 1270 57


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