Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that kainate (KA) receptors are involved in neuronal cell death induced by seizure, which is mediated by the GluR6.PSD-95.MLK3 signaling module and subsequent JNK activation. In our previous studies, we demonstrated the neuroprotective role of a GluR6 c-terminus containing peptide against KA or cerebral ischemia-induced excitotoxicity in vitro and in vivo. Here, we first report that overexpression of the PDZ1 domain of PSD-95 protein exerts a protective role against neuronal death induced by cerebral ischemia-reperfusion in vivo and can prevent neuronal cell death induced by oxygen-glucose deprivation. Further studies show that overexpression of PDZ1 can perturb the interaction of GluR6 with PSD-95 and suppress the assembly of the GluR6.PSD-95.MLK3 signaling module and therefore inhibit JNK activation. Thus, it not only inhibits phosphorylation of c-Jun and down-regulates Fas ligand expression but also inhibits phosphorylation of 14-3-3 and decreases Bax translocation to mitochondria, decreases the release of cytochrome c, and decreases caspase-3 activation. Overall, the essential role of the PDZ1 domain of PSD-95 in apoptotic cell death in neurons provides an experimental foundation for gene therapy of neurodegenerative diseases with overexpression of the PDZ1 domain.
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PMID:Overexpression of the PDZ1 domain of PSD-95 diminishes ischemic brain injury via inhibition of the GluR6.PSD-95.MLK3 pathway. 1961 93

The adaptor protein CARMA1 is required for antigen receptor-triggered activation of IKK and JNK in lymphocytes. Once activated, the events that subsequently turn off the CARMA1 signalosome are unknown. In this study, we found that antigen receptor-activated CARMA1 underwent lysine 48 (K48) polyubiquitination and proteasome-dependent degradation. The MAGUK region of CARMA1 was an essential player in this event; the SH3 and GUK domains contained the main ubiquitin acceptor sites, and deletion of a Hook domain (an important structure for maintaining inactive MAGUK proteins) between SH3 and GUK was sufficient to induce constitutive ubiquitination of CARMA1. A similar deletion promoted the ubiquitination of PSD-95 and Dlgh1, suggesting that a conserved mechanism may control the turnover of other MAGUK family protein complexes. Functionally, we demonstrated that elimination of MAGUK ubiquitination sites in CARMA1 resulted in elevated basal and inducible NF-kappaB and JNK activation as a result of defective K48 ubiquitination and increased persistence of this ubiquitination-deficient CARMA1 protein in activated lymphocytes. The coordination of degradation with the full activation of the CARMA1 molecule likely provides an intrinsic feedback control mechanism to balance lymphocyte activation upon antigenic stimulation.
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PMID:MAGUK-controlled ubiquitination of CARMA1 modulates lymphocyte NF-kappaB activity. 2000 54

Estrogen modulates synaptic plasticity, an important mechanism of memory storage. Previously, we have reported that estrogen rapidly increases the expression of Arc (activity-regulated cytoskeleton associated protein), a key protein for synaptic plasticity, via non-genomic phosphoinositide-3 kinase (PI-3K)-, mitogen-activated protein kinase (MAPK)-, and estrogen receptor (ER)-dependent pathways in SH-SY5Y cells. The present study aimed to investigate the role of each ER subtype, alpha and beta, in synaptic plasticity in SH-SY5Y cells. The specific agonist of ER beta (DPN) markedly induced Arc expression that mimics treatment with estrogen, but not ER alpha (PTT). Determination of subcellular localization of ER beta using immunocytochemistry shows that ER beta was retained in the cytoplasm of the untreated cells. In estrogen-treated cells, the membrane and cytosolic ER beta gradually decreased, while nuclear ER beta progressively increased in time-dependent manner, suggesting estrogen-dependent nuclear translocation of ER beta. Nuclear accumulation of ER beta at 6-12h post-estrogen treatment, leads to increased PSD-95 and SYP mRNA expression, indicating the classical genomic estrogenic action on synaptic plasticity. However, the block of PI-3K signaling by Wortmannin partially suppressed estrogen (48 h)-induced PSD-95 and SYP expression, suggesting a crosstalk mechanism between genomic and non-genomic actions of estrogen on synaptic plasticity. Therefore, the estrogen-enhanced synaptic plasticity is ER beta-dependent and involves the crosstalk mechanism of non-genomic and genomic estrogenic actions.
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PMID:Genomic and non-genomic actions of estrogen on synaptic plasticity in SH-SY5Y cells. 2003 14

Post-synaptic density protein PSD-95 is emerging as a valid target for modulating nociception in animal studies. Based on the key role of PSD-95 in neuronal plasticity and the maintenance of pain behavior, we predicted that CN2097, a peptide-based macrocycle of nine residues that binds to the PSD-95 Discs large, Zona occludens 1 (PDZ) domains of PSD-95, would interfere with physiologic phenomena in the spinal cord related to central sensitization. Furthermore, we tested whether spinal intrathecal injection of CN2097 attenuates thermal hyperalgesia in a rat model of sciatic neuropathy. Results demonstrate that spinal CN2097 reverses hyperexcitability of wide dynamic range (WDR) neurons in the dorsal horn of neuropathic rats and decreases their evoked responses to peripheral stimuli (brush, low caliber von Frey and pressure), whereas CN5125 ("negative control") has no effect. CN2097 also blocks C-fiber long-term potentiation (LTP) in the dorsal horn, which is linked to neuronal plasticity and central sensitization. At a molecular level, CN2097 attenuates the increase in phosphorylated p38 MAPK, a key intracellular signaling pathway in neuropathic pain. Moreover, spinal injection of CN2097 blocks thermal hyperalgesia in neuropathic rats. We conclude that CN2097 is a small molecule peptide with putative anti-nociceptive effects that modulates physiologic phenomena related to central sensitization under conditions of chronic pain.
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PMID:A cyclic peptide targeted against PSD-95 blocks central sensitization and attenuates thermal hyperalgesia. 2016 66

Our latest study indicated that ethanol could attenuate cerebral ischemia/reperfusion-induced brain injury through activating Ionotropic glutamate receptors Kainate Family (Gluk1)-kainate (KA) receptors and gamma-aminobutyric acid (GABA) receptors. However, the possible mechanism of the neuroprotective effects of ethanol remains unclear. In this study we report that ethanol shows neuroprotective effects against ischemic brain injury through enhancing GABA release and then decreasing c-Jun N-terminal kinase 3 (JNK3) activation. Electrophysiologic recording indicated that ethanol enhances GABA release from presynaptic neurons and the released GABA subsequently inhibits the KA receptor-mediated whole-cell currents. Moreover, our data show that ethanol can inhibit the increased assembly of the Gluk2-PSD-95-MLK3 (postsynaptic density protein-95, PSD-95 and mixed-lineage kinase 3, MLK3) module induced by cerebral ischemia and the activation of the MLK3-MKK4/7-JNK (mitogen-activated protein kinase kinase 4/7, MKK4/7) cascade. Pretreatment of the GABA(A) receptor antagonist bicuculline and antagonist of VGCC (a broad-spectrum blocker of the voltage-gated calcium channel [VGCC]) Chromic (CdCl(2)) can demolish the neuroprotective effects of ethanol. The results suggest that during ischemia-reperfusion, ethanol may activate presynaptic Gluk1-KA and facilitate Ca(2+)-dependent GABA release. The released GABA activates postsynaptic GABA(A) receptors, which suppress the ischemic depolarization and decrease the association of signaling module Gluk2-PSD-95-MLK3 induced by the activation of postsynaptic Gluk2-KA receptors. There is a raised possibility that ethanol inhibiting the JNK3 apoptotic pathway (MLK3/MKK4/7/JNK3/c-Jun/Fas-L) performs a neuroprotective function against ischemic brain injury.
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PMID:Neuroprotection of ethanol against ischemia/reperfusion-induced brain injury through decreasing c-Jun N-terminal kinase 3 (JNK3) activation by enhancing GABA release. 2021 37

The beta-2 adrenergic receptor (beta2AR) has a carboxyl terminus motif that can interact with PSD-95/discs-large/ZO1 homology (PDZ) domain-containing proteins. In this paper, we identified membrane-associated guanylate kinase inverted-3 (MAGI-3) as a novel binding partner of beta2AR. The carboxyl terminus of beta2AR binds with high affinity to the fifth PDZ domain of MAGI-3, with the last four amino acids (D-S-L-L) of the receptor being the key determinants of the interaction. In cells, the association of full-length beta2AR with MAGI-3 occurs constitutively and is enhanced by agonist stimulation of the receptor. Our data also demonstrated that beta2AR-stimulated extracellular signal-regulated kinase-1/2 (ERK1/2) activation was substantially retarded by MAGI-3 expression. These data suggest that MAGI-3 regulates beta2AR-mediated ERK activation through the physical interaction between beta2AR and MAGI-3.
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PMID:Beta-2 adrenergic receptor mediated ERK activation is regulated by interaction with MAGI-3. 2035 89

In vitro expansion of neural stem cells (NSC) lentivirally transduced with human BDNF may serve as better cellular source for replacing degenerating neurons in disease, trauma and toxic insults. In this study, we evaluate the functional role of forced BDNF expression by means of NSC (M3GFP-BDNF) obtained from cerebral cortex of 1-day-old mice respect to NSC-control (M3GFP). We find that M3GFP-BDNF induced to differentiate significantly accumulate BDNF and undergone to high potassium-mediated depolarization, show rapid BDNF recycle and activation of Trk receptors signaling. Differentiated M3GFP-BDNF exhibit neurons and oligodendrocytes with extended processes although quantitative analyses of NSC-derived cell lineages show none statistical significance between both cell populations. Moreover, those cells show a significant induction of neuronal and oligodendroglial markers by RT-PCR and Western blot respect to M3GFP, such as betaIII-Tubulin, microtubule associated protein 2 (MAP2), neurofilaments heavy (NF-H), oligodendroglial myelin glycoprotein (OMG) and some molecules involved in glutamatergic synapse maturation, such as receptors tyrosine kinases (TRKs), post-synaptic density (PSD-95) and N-methyl-D-aspartate receptors 2 A/B (NMDA2A/B). After treatment with the neurotoxicant trimethyltin (TMT), differentiated M3GFP-BDNF exhibit an attenuation of cellular damage which correlates with a significant activation of MAPK and PI3K/Akt signaling and delayed activation of death signals, while on M3GFP, TMT induces a significant reduction of cell survival, neuronal differentiation and concomitant earlier activation of cleaved caspase-3. We demonstrate that overexpression of BDNF firmly regulate cell survival and differentiation of NSC and protects differentiated NSC against TMT-induced neurotoxicity through the PI3K/Akt and MAPK signaling pathways.
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PMID:Neural stem cells modified to express BDNF antagonize trimethyltin-induced neurotoxicity through PI3K/Akt and MAP kinase pathways. 2043 66

D-galactose-(D-gal)-treated mouse, with cognitive impairment, has been used for neurotoxicity investigation and anti-neurotoxicity pharmacology research. In this study, we investigated the mechanism underlying the neuroprotective effect of troxerutin. The results showed that troxerutin improved behavioral performance in D-gal-treated mice by elevating Cu, Zn-superoxide dismutases (Cu, Zn-SOD) activity and decreasing reactive oxygen species levels. Furthermore, our results showed that troxerutin significantly promoted nerve growth factor (NGF) mRNA expression which resulted in TrkA activation. On one hand, NGF/TrkA induced activation of Akt and ERK1/2, which led to neuronal survival; on the other hand, NGF/TrkA mediated CaMKII and CREB phosphorylation and increased PSD95 expression, which improved cognitive performance. However, the neuroprotective effect of troxerutin was blocked by treatment with K252a, an antagonist for TrkA. No neurotoxicity was observed in mice treated with K252a or troxerutin alone. In conclusion, administration of troxerutin to D-gal-injected mice attenuated cognitive impairment and brain oxidative stress through the activation of NGF/TrkA signaling pathway.
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PMID:NGF-Dependent activation of TrkA pathway: A mechanism for the neuroprotective effect of troxerutin in D-galactose-treated mice. 2045 66

Interleukin-1-Receptor Accessory Protein Like 1 (IL1RAPL1) gene mutations are associated to cognitive impairment ranging from non-syndromic X-linked mental retardation to autism. Functionally IL1RAPL1 belongs to a novel family of Toll/IL-1 Receptors, but its ligand is unknown. In a recent study, we have shown that IL1RAPL1 is present in dendritic spine where it interacts with PSD-95, a major scaffold protein of excitatory post-synaptic density. We demonstrated that IL1RAPL1 regulates the synaptic localization of PSD-95 by controlling JNK (c-Jun terminal Kinase) activity and PSD-95 phosphorylation. Loss of IL1RAPL1 in mouse not only led to a reduction of excitatory synapses but also to specific deficits in hippocampal long-term synaptic plasticity. Here we report that activation of JNK pathway in neurons by Interleukin-1 (IL-1) is mediated by IL1RAPL1. The interaction of IL1RAPL1 with PSD-95 discloses a novel pathophysiological mechanism underlying cognitive impairment associated with alterations of the JNK pathway in response to IL-1 and leading to the mislocalization of PSD-95, that subsequently result in abnormal synaptic organization and function.
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PMID:Neuronal JNK pathway activation by IL-1 is mediated through IL1RAPL1, a protein required for development of cognitive functions. 2071 5

Although recent results suggest that GluR6 serine phosphorylation plays a prominent role in brain ischemia/reperfusion-mediated neuronal injury, little is known about the precise mechanisms regulating GluR6 receptor phosphorylation. Our present study shows that the assembly of the GluR6-PSD95-CaMKII signaling module induced by brain ischemia facilitates the serine phosphorylation of GluR6 and further induces the activation of c-Jun NH2-terminal kinase JNK. More important, a selective CaMKII inhibitor KN-93 suppressed the increase of the GluR6-PSD95-CaMKII signaling module assembly and GluR6 serine phosphorylation as well as JNK activation. Such effects were similar to be observed by NMDA receptor antagonist MK801 and L-type Ca(2+) channel (L-VGCC) blocker Nifedipine. These results demonstrate that NMDA receptors and L-VGCCs depended-CaMKII functionally modulated the phosphorylation of GluR6 via the assembly of GluR6-PSD95-CaMKII signaling module in cerebral ischemia injury.
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PMID:Calcium/calmodulin-dependent kinase II facilitated GluR6 subunit serine phosphorylation through GluR6-PSD95-CaMKII signaling module assembly in cerebral ischemia injury. 2088 27


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