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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The NMDA subtype of glutamate receptors (NMDAR) at excitatory neuronal synapses plays a key role in synaptic plasticity. The extracellular signal-regulated kinase (ERK1,2 or ERK) pathway is an essential component of NMDAR signal transduction controlling the neuroplasticity underlying memory processes, neuronal development, and refinement of synaptic connections. Here we show that NR2B, but not NR2A or NR1 subunits of the NMDAR, interacts in vivo and in vitro with RasGRF1, a Ca(2+)/calmodulin-dependent Ras-guanine-nucleotide-releasing factor. Specific disruption of this interaction in living neurons abrogates NMDAR-dependent ERK activation. Thus, RasGRF1 serves as NMDAR-dependent regulator of the ERK kinase pathway. The specific association of RasGRF1 with the NR2B subunit and study of ERK activation in neurons with varied content of NR2B suggests that NR2B-containing channels are the dominant activators of the NMDA-dependent ERK pathway.
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PMID:The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. 1462 81

Glutamate receptor activation of mitogen-activated protein (MAP) kinase signalling cascades has been implicated in diverse neuronal functions such as synaptic plasticity, development and excitotoxicity. We have previously shown that Ca2+-influx through NMDA receptors in cultured striatal neurones mediates the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt/protein kinase B (PKB) through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. Exposing neurones to the Src family tyrosine kinase inhibitor PP2, but not the inactive analogue PP3, inhibited NMDA receptor-induced phosphorylation of ERK1/2 and Akt/PKB in a concentration-dependent manner, and reduced cAMP response element-binding protein (CREB) phosphorylation. To establish a link between Src family tyrosine kinase-mediated phosphorylation and PI 3-kinase signalling, affinity precipitation experiments were performed with the SH2 domains of the PI 3-kinase regulatory subunit p85. This revealed a Src-dependent phosphorylation of a focal adhesion kinase (FAK)-p85 complex on glutamate stimulation. Demonstrating that PI3-kinase is not ubiquitously involved in NMDA receptor signal transduction, the PI 3-kinase inhibitors wortmannin and LY294002 did not prevent NMDA receptor Ca2+-dependent phosphorylation of c-Jun N-terminal kinase 1/2 (JNK1/2). Further, inhibiting Src family kinases increased NMDA receptor-dependent JNK1/2 phosphorylation, suggesting that Src family kinase-dependent cascades may physiologically limit signalling to JNK. These results demonstrate that Src family tyrosine kinases and PI3-kinase are pivotal regulators of NMDA receptor signalling to ERK/Akt and JNK in striatal neurones.
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PMID:Inhibiting Src family tyrosine kinase activity blocks glutamate signalling to ERK1/2 and Akt/PKB but not JNK in cultured striatal neurones. 1500 68

Cyclic AMP-specific phosphodiesterase 4 (PDE4), which is an integral component of NMDA receptor-mediated cAMP signaling, is involved in the mediation of memory processes. Given that NMDA receptors also mediate MEK/mitogen-activated protein kinase (MAPK, ERK) signaling, which is involved in synaptic plasticity, and that some PDE4 subtypes are phosphorylated and regulated by ERK, it was of interest to determine if PDE4 is involved in MEK/ERK signaling-mediated memory. It was found that rolipram, a PDE4-selective inhibitor, reversed the amnesic effect in the radial-arm maze test of the MEK inhibitor U0126 administered into the CA1 subregion of the rat hippocampus. Consistent with this, rolipram, either by peripheral administration or direct intra-CA1 infusion, enhanced the retrieval of long-term memory impaired by intra-CA1 infusion of U0126 using the step-through inhibitory avoidance test. The same dose of rolipram did not affect U0126-induced reduction of phospho-ERK1/2 levels in the CA1 subregion. However, in primary cultures of rat cerebral cortical neurons, pretreatment with U0126 increased PDE4 activity; this was correlated with the U0126-induced reduction of phospho-ERK1/2 levels. These results suggest that MEK/ERK signaling plays an inhibitory role in regulating PDE4 activity in the brain; this may be a novel mechanism by which MEK/ERK signaling mediates memory. PDE4 is likely to be an important link between the cAMP/PKA and MEK/ERK signaling pathways in the mediation of memory.
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PMID:Inhibition of the phosphodiesterase 4 (PDE4) enzyme reverses memory deficits produced by infusion of the MEK inhibitor U0126 into the CA1 subregion of the rat hippocampus. 1511 41

Circadian rhythms of physiology and behavior are generated by biological clocks that are synchronized to the cyclic environment by photic or nonphotic cues. The interactions and integration of various entrainment pathways to the clock are poorly understood. Here, we show that the Ras-like G protein Dexras1 is a critical modulator of the responsiveness of the master clock to photic and nonphotic inputs. Genetic deletion of Dexras1 reduces photic entrainment by eliminating a pertussis-sensitive circadian response to NMDA. Mechanistically, Dexras1 couples NMDA and light input to Gi/o and ERK activation. In addition, the mutation greatly potentiates nonphotic responses to neuropeptide Y and unmasks a nonphotic response to arousal. Thus, Dexras1 modulates the responses of the master clock to photic and nonphotic stimuli in opposite directions. These results identify a signaling molecule that serves as a differential modulator of the gated photic and nonphotic input pathways to the circadian timekeeping system.
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PMID:Dexras1 potentiates photic and suppresses nonphotic responses of the circadian clock. 1533 41

Molecular mechanisms underlying C-fiber stimulation-induced ERK (extracellular signal-regulated kinase) activation in dorsal horn neurons and its contribution to central sensitization have been investigated. In adult rat spinal slice preparations, activation of C-fiber primary afferents by a brief exposure of capsaicin produces an eightfold to 10-fold increase in ERK phosphorylation (pERK) in superficial dorsal horn neurons. The pERK induction is reduced by blockade of NMDA, AMPA/kainate, group I metabotropic glutamate receptor, neurokinin-1, and tyrosine receptor kinase receptors. The ERK activation produced by capsaicin is totally suppressed by inhibition of either protein kinase A (PKA) or PKC. PKA or PKC activators either alone or more effectively together induce pERK in superficial dorsal horn neurons. Inhibition of calcium calmodulin-dependent kinase (CaMK) has no effect, but pERK is reduced by inhibition of the tyrosine kinase Src. The induction of cAMP response element binding protein phosphorylation (pCREB) in spinal cord slices in response to C-fiber stimulation is suppressed by preventing ERK activation with the MAP kinase kinase inhibitor 2-(2-diamino-3-methoxyphenyl-4H-1-benzopyran-4-one (PD98059) and by PKA, PKC, and CaMK inhibitors. Similar signaling contributes to pERK induction after electrical stimulation of dorsal root C-fibers. Intraplantar injection of capsaicin in an intact animal increases expression of pCREB, c-Fos, and prodynorphin in the superficial dorsal horn, changes that are prevented by intrathecal injection of PD98059. Intrathecal PD98059 also attenuates capsaicin-induced secondary mechanical allodynia, a pain behavior reflecting hypersensitivity of dorsal horn neurons (central sensitization). We postulate that activation of ionotropic and metabotropic receptors by C-fiber nociceptor afferents activates ERK via both PKA and PKC, and that this contributes to central sensitization through post-translational and CREB-mediated transcriptional regulation in dorsal horn neurons.
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PMID:Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. 1538 14

Fructose-1,6-bisphosphate (FBP) is a glucose metabolism intermediate that shows a neuroprotective action in animal models of ischemia and other injuries. The intracellular mechanism of FBP on neuroprotection has not been previously defined. Here, we examined whether FBP has a neuroprotective effect against excitotoxicity, and whether it affects the production of reactive oxygen species (ROS), which are involved in the MAPK pathway in cortical neurons. FBP prevented neuronal death in a dose-dependent manner following 24 h of treatment with the excitotoxin, NMDA. After 8 h of NMDA treatment, we observed FBP-induced inhibition of the production of intracellular ROS, and at the earlier time FBP suppressed NMDA-induced p-p38 and p-ERK expression. In addition, MAPK inhibitors reduced NMDA-induced excitotoxicity and also ROS production. Taken together, our results suggest that the neuroprotective effects of FBP could be explained by down-regulation of free radical production through the p38MAPK/ERK pathway.
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PMID:Neuroprotection by fructose-1,6-bisphosphate involves ROS alterations via p38 MAPK/ERK. 1548 92

The specification and organization of glutamatergic synaptic transmission require the coordinated interaction among glutamate receptors and their synaptic adaptor proteins closely assembled in the postsynaptic density (PSD). Here we investigated the interaction between NMDA receptors and metabotropic glutamate receptor 5 (mGluR5) in the integral regulation of extracellular signal-regulated protein kinase (ERK) and gene expression in cultured rat striatal neurons. We found that coapplication of NMDA and the mGluR5 agonist (S)-3,5-dihydroxyphenylglycine synergistically increased ERK phosphorylation. Interestingly, the synergistic increase in ERK phosphorylation was dependent on the cross talk between NMDA receptor-associated synaptic adaptor protein PSD-95 and the mGluR5-linked adaptor protein Homer1b/c but not on the conventional Ca2+ signaling derived from NMDA receptors (Ca2+ influx) and mGluR5 (intracellular Ca2+ release). This was demonstrated by the findings that the synergistic phosphorylation of ERK induced by coactivation of NMDA receptors and mGluR5 was blocked by either a Tat peptide that disrupts NMDA receptor/PSD-95 binding or small interfering RNAs that selectively reduce cellular levels of Homer1b/c. Furthermore, ERK activated through this PSD-95/Homer1b/c-dependent and Ca2+-independent pathway was able to phosphorylate the two key transcription factors Elk-1 and cAMP response element-binding protein, which further leads to facilitation of c-Fos expression. Together, we have identified a novel Ca2+-independent signaling pathway to ERK by the synergistic interaction of NMDA receptors and mGluR5 via their adaptor proteins in the PSD of neurons, which underlies a synapse-to-nucleus communication important for the transcriptional regulation.
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PMID:A novel Ca2+-independent signaling pathway to extracellular signal-regulated protein kinase by coactivation of NMDA receptors and metabotropic glutamate receptor 5 in neurons. 1557 35

Several experiments explored the roles of nucleus accumbens (NA), ventral pallidum (VP) and medial preoptic area (MPOA) in the regulation of maternal behavior in rats. A preliminary experiment found that bilateral radiofrequency lesions of medial NA did not disrupt maternal behavior. Experiment 1 found that bilateral infusions of muscimol into VP, but not into medial NA, reversibly disrupted maternal behavior. Experiment 2 found that unilateral muscimol injections into VP disrupted maternal behavior to a greater extent when paired with a contralateral N-methyl-d-aspartic acid (NMDA) MPOA lesion than when paired with a sham MPOA lesion. Experiment 3 showed that a unilateral NMDA MPOA lesion paired with a contralateral NMDA VP lesion (Contra group) disrupted maternal behavior to a much greater extent than did sham NMLA lesions or NMDA lesions of MPOA and VP ipsilateral to one another. Experiment 3 focused on the specificity of the maternal behavior disruptions and found that the primary maternal deficit in the Contra females was a severe deficit in retrieval behavior. Importantly, these females showed normal hoarding behavior, home cage activity, and elevated plus maze activity. Experiment 3 used Neu N immunohistochemistry to define the extent of MPOA and VP excitotoxic lesions. It is hypothesized that MPOA acts to facilitate the active components of maternal behavior by inhibiting NA, which then releases VP from GABAergic inhibition, and such disinhibition of VP allows pup stimuli to trigger appropriate maternal responses.
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PMID:Medial preoptic area interactions with the nucleus accumbens-ventral pallidum circuit and maternal behavior in rats. 1568 Jan 94

Calcium regulation of several transcription factors involves different calcium-dependent signaling cascades and engages cytoplasmic as well as nuclear calcium signals. The study of the specific sources of calcium signals involved in regulation of gene expression in skeletal muscle has been addressed only recently. In this tissue, most cytoplasmic and nuclear calcium signals originate from calcium release from internal stores, mediated either by ryanodine receptor (RyR) or IP3 receptor (IP3R) channels. The latter are located both in the sarcoplasmic reticulum (SR) and in the nuclear membrane, and their activation results in long-lasting nuclear calcium increase. The calcium signals mediated by RyR and IP3R are very different in kinetics, amplitude and subcellular localization; an open question is whether these differences are differentially sensed by transcription factors. In neurons, it is well established that calcium entry through L-type calcium channels and NMDA receptors plays a role in the regulation of gene expression. Increasing evidence, however, points to a role for calcium release from intracellular stores in this process. In this article, we discuss how RyR-mediated calcium release contributes to the activation of the calcium-dependent transcription factor CREB and the subsequent LTP generation. We present novel results from our laboratory showing ERK-mediated CREB activation by hydrogen peroxide. This activation takes place in the absence of extracellular calcium and is blocked by inhibitory ryanodine concentrations, suggesting it is caused by redox activation of RyR-mediated calcium release.
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PMID:Signal transduction and gene expression regulated by calcium release from internal stores in excitable cells. 1570

Apolipoprotein E is a genetic risk factor for Alzheimer's disease, and the apoE protein is associated with beta-amyloid deposits in Alzheimer's disease brain. We examined signaling pathways stimulated by apoE in primary neurons in culture. ApoE and an apoE-derived peptide activated several intracellular kinases, including prominently extracellular signal-regulated kinase 1/2 (ERK1/2). ERK1/2 activation by apoE was blocked by an inhibitor of the low-density lipoprotein receptor family, the specific NMDA glutamate receptor antagonist MK 801 and other calcium channel blockers. Activation of apoE receptors also induced tyrosine phosphorylation of Dab1, an adaptor protein of apoE receptors, but experiments in Dab1 knockout neurons demonstrated that Dab1 was not necessary for ERK activation. In contrast, apoE treatment of primary neurons decreased activation of c-Jun N-terminal kinase, a kinase that interacts with another apoE receptor adaptor protein, c-Jun N-terminal kinase-interacting protein. This change also depended on interactions with the low-density lipoprotein receptor family but was independent of calcium channels. c-Jun N-terminal kinase deactivation by apoE was blocked by gamma-secretase inhibitors and pertussis toxin. These results demonstrate that apoE affects several signaling cascades in neurons: increased disabled phosphorylation, activation of the ERK1/2 pathway (dependent on calcium influx via the NMDA receptor) and inhibition of the c-Jun N-terminal kinase 1/2 pathway (dependent on gamma-secretase and G proteins).
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PMID:Multiple pathways of apolipoprotein E signaling in primary neurons. 1577 14


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