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)

Cocaine is an addictive psychostimulant that induces immediate early gene (IEG) expression by activating dopamine (DA) D1 and glutamate NMDA receptors in the striatum. In this study, we show that a single cocaine administration (30 mg/kg) time-dependently increases ERK phosphorylation, c-Fos and FosB protein expression, and MKP-1 phosphorylation (p-MKP-1), in the caudate-putamen (CPu) and nucleus accumbens (NAc) of Fischer rats. In the CPu, 1 h after cocaine injection, the increase in c-Fos and FosB protein expressions is totally abolished by pre-administration of DA-D1 receptor antagonist, SCH23390. In the NAc, SCH23390 also inhibits cocaine-induced c-Fos protein expression. The pre-treatment of NMDA receptor antagonist, MK801, partially reduces cocaine-activated c-Fos protein expression in the CPu. Furthermore, the escalation of p-MKP-1 after acute cocaine administration is dependent on both DA-D1 and NMDA receptor activation in both brain regions examined. Our data suggest that cocaine may modulate ERK pathway signaling through the activation of DA-D1 and NMDA receptors, subsequently influencing the IEG protein expression.
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PMID:Effects of dopamine and NMDA receptors on cocaine-induced Fos expression in the striatum of Fischer rats. 1882 74

Cognitive functions are thought to deteriorate globally in late stages of various neurodegenerative disorders. Here we describe that this general assumption is not justified and fails in Huntington's disease (HD). Presymptomatic gene mutation carriers (pHDs) and healthy controls performed worse compared with symptomatic HDs in an auditory signal detection task. During task performance, behavioral data and event-related potentials (ERPs) [i.e., MMN (mismatch negativity), P3a, and RON (reorienting negativity)] were recorded. Not only behavioral performance but also neurophysiological correlates of auditory sensory memory and attentional reorientation indicate enhanced performance occurring primal in late stages of a neurodegenerative disorder. Increased activity of the NMDA-receptor system, an assumed pathogenic mechanism in HD, might facilitate signal propagation at striatal level that enables more efficient task execution through a winner-take-all process. The results challenge the view that late stage neurodegeneration is necessarily related to a global decline in cognitive abilities in HD. In contrast, selectively enhanced cognitive functioning can emerge together with otherwise impaired cognitive functioning.
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PMID:Increased cognitive functioning in symptomatic Huntington's disease as revealed by behavioral and event-related potential indices of auditory sensory memory and attention. 1898 5

N-methyl-d-aspartate receptors (NMDAR) are tetrameric amino acid receptors which act as membrane calcium channels. The presence of the receptor has been detected in the principal organs responsible for calcium homeostasis (kidney and bone), pointing to a possible role in mineral metabolism. In the present work, the presence of the receptor was determined in normal parathyroid glands (PTG) by real-time PCR, immunoprecipitation, and immunohistrochemistry. Healthy animals showed a decrease in blood parathyroid hormone (PTH) levels 15 min after the treatment with NMDA. This effect was also observed in animals with high levels of PTH-induced EDTA injection, but not in uremic animals with secondary hyperparathyroidism (2HPT). Normal rat PTG incubated in media with low calcium concentration (0.8 mM CaCl2) showed a decrease in PTH release when NMDA was added to the media. This effect of NMDA was abolished when glands were coincubated with MK801 (a pharmacological blocker of the NMDA channel) or PD98059 (an inhibitor of the ERK-MAPK pathway). Glands obtained from animals with 2HPT showed no effect of NMDA in the in vitro release of PTH, together with a decrease in the expression of NMDAR1. In conclusion, NMDA receptor is present in PTG and is involved in the regulation of the PTH release. The mechanism by which NMDAR exerts its function is through the activation of the MAPK cascade. In uremic 2HPT animals the receptor expression is downregulated and the treatment with NMDA does not affect PTH secretion.
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PMID:N-methyl-D-aspartate receptors are expressed in rat parathyroid gland and regulate PTH secretion. 1935 80

The general features of neuroplasticity are developmentally regulated. Although it has been hypothesized that the loss of plasticity in mature neurons may be due to synaptic saturation and functional reduction of N-methyl-D-aspartate receptors (NMDAR), the molecular mechanisms remain largely unknown. We examined the effects of NMDAR activation and KCl-mediated membrane depolarization on ERK1/2 signaling following in vitro maturation of cultured cortical neurons. Although NMDA stimulated a robust increase in intracellular calcium at both DIV (day in vitro) 3 and 14, the activation of ERK1/2 and cAMP responsive element-binding protein (CREB) was impaired at DIV 14. Specifically, the phosphorylation of ERK1/2 was stimulated by both NMDA and KCl at DIV 3. However, at DIV 14, NMDA- but not KCl-stimulated ERK1/2 and CREB phosphorylation was significantly diminished. Consistently, the NMDA-induced transcription of ERK/CREB-regulated genes Bdnf exon 4, Arc, and zif268 was significantly attenuated at DIV 14. Moreover, in comparison with 3 DIV neurons, the phosphorylated-ERK1/2 in 14 DIV neurons displayed a tremendous increase following maturation and was more susceptible to dephosphorylation. Blocking calcium channels by nifedipine or NMDAR by APV caused a more dramatic ERK dephosphorylation in 14 DIV neurons. We further demonstrate that the loss of plasticity-related signaling is unrelated to NMDA-induced cell death of the 14 DIV neurons. Taken together, these results suggest that the attenuation of certain aspects of neuroplasticity following maturation may be due to the reduction of NMDAR-mediated gene transcription and a saturation of ERK1/2 activity.
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PMID:N-methyl-D-aspartate-stimulated ERK1/2 signaling and the transcriptional up-regulation of plasticity-related genes are developmentally regulated following in vitro neuronal maturation. 1939 76

Activity-dependent transcriptional up-regulation of bdnf (brain-derived neurotrophic factor) is involved in regulating many aspects of neuronal functions. The NMDA (N-methyl-D-aspartic acid)-mediated and BDNF-mediated exon IV transcription may represent mechanistically different responses, and relevant to activity-dependent changes in neurons. We found that the activities of ERK (extracellular signal regulated kinase), CaM KII/IV (calmodulin-dependent protein kinase II and IV), PI3K (phosphoinositide 3-kinase), and PLC (phospholipase C) are required for NMDA receptor-mediated bdnf exon IV transcription in cultured cortical neurons. In contrast, the BDNF-induced and TrkB-dependent exon IV transcription was regulated by ERK and CaM KII/IV, but not by PI3K and PLC. While ERK and CaM KII/IV are separate signaling pathways in BDNF-stimulated neurons, CaM KII/IV appeared to regulate exon IV transcription through ERK in NMDA-stimulated neurons. Similarly, the PI3K and PLC signaling pathways converged on ERK in NMDA- but not BDNF-stimulated neurons. Our results implicate that the NMDA-induced and the self-maintenance of bdnf transcription are differentially regulated.
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PMID:NMDA-mediated and self-induced bdnf exon IV transcriptions are differentially regulated in cultured cortical neurons. 1941 34

Cell adhesion molecules at neuronal synapses regulate diverse aspects of synaptic development, including axo-dendritic contact establishment, early synapse formation, and synaptic maturation. Recent studies have identified several synaptogenic adhesion molecules. The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively. NGLs interact with the abundant postsynaptic density (PSD) protein, PSD-95, and other postsynaptic proteins, including NMDA receptors. These interactions are thought to couple synaptic adhesion events to the assembly of synaptic proteins. In addition, NGL proteins regulate axonal outgrowth and lamina-specific dendritic segmentation, suggesting that the NGL-dependent adhesion system is important for the development of axons, dendrites, and synapses. Consistent with these functions, defects in NGLs and their ligands are associated with impaired learning and memory, hyperactivity, and an abnormal acoustic startle response in transgenic mice, and schizophrenia, bipolar disorder, and Rett syndrome in human patients.
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PMID:The NGL family of leucine-rich repeat-containing synaptic adhesion molecules. 1946 32

Brain lesions induced in newborn mice by the glutamatergic agonists ibotenate (acting on NMDA and metabotropic receptors) or S-willardiine (acting on AMPA-kainate receptors) mimic some aspects of periventricular white matter lesions and neocortical grey matter damage observed in human neonates at risk for developing cerebral palsy. The neonatal mouse brain can be sensitized to excitotoxic damage by IL-1beta exposure similar to that observed in the human situation. Positive modulators of AMPA receptors have received increasing attention as potential neuroprotective agents in a number of neurodegenerative disorders of the adult. However whether they can also act as a neuroprotectant in neonatal brain damage has yet to be defined. Therefore the present study uses a well-defined rodent model of neonatal excitotoxic brain lesions to assess the neuroprotective effects of S18986, a positive allosteric modulator of AMPA receptors, as well as its mechanisms of action. In this model, S18986 provided a dose-dependent and long-lasting protection of developing white matter and cortical grey matter against an excitotoxic insult and also when this was combined with a sensitizing inflammatory insult. Neuroprotective effects of S18986 in cortical grey matter involved decreased necrotic and apoptotic cell death. S18986-induced neuroprotection against NMDA receptor-mediated brain lesions was blocked by inhibitors of ERK and PI3 kinase-Akt pathways. S18986 effects were abolished by a neutralizing anti-BDNF antibody and real time PCR confirmed the stimulation by S18986 of BDNF production in the neonatal brain. The present study provides strong experimental support for the role of S18986 as a candidate molecule for therapy in cases of excitotoxic perinatal brain lesions and identifies BDNF as a key mediator of this S18986-mediated neuroprotection.
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PMID:The AMPA receptor positive allosteric modulator, S18986, is neuroprotective against neonatal excitotoxic and inflammatory brain damage through BDNF synthesis. 1950 Nov 11

Hyperhomocysteinemia is an independent risk factor for stroke and neurological abnormalities. However, the underlying cellular mechanisms by which elevated homocysteine can promote neuronal death is not clear. In the present study we have examined the role of NMDA receptor-mediated activation of the extracellular signal-regulated kinase-mitogen-activated protein (ERK-MAP) kinase pathway in homocysteine-dependent neurotoxicity. The study demonstrates that in neurons l-homocysteine-induced cell death was mediated through activation of NMDA receptors. The study also shows that homocysteine-dependent NMDA receptor stimulation and resultant Ca2+ influx leads to rapid and sustained phosphorylation of ERK-MAP kinase. Inhibition of ERK phosphorylation attenuates homocysteine-mediated neuronal cell death thereby demonstrating that activation of ERK-MAP kinase signaling pathway is an intermediate step that couples homocysteine-mediated NMDA receptor stimulation to neuronal death. The findings also show that cAMP response-element binding protein (CREB), a pro-survival transcription factor and a downstream target of ERK, is only transiently activated following homocysteine exposure. The sustained activation of ERK but a transient activation of CREB together suggest that exposure to homocysteine initiates a feedback loop that shuts off CREB signaling without affecting ERK phosphorylation and thereby facilitates homocysteine-mediated neurotoxicity.
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PMID:Homocysteine-NMDA receptor-mediated activation of extracellular signal-regulated kinase leads to neuronal cell death. 1950 27

The biochemical and pharmacological activities of nobiletin, including neurotrophic and memory-enhancing action, in both in vitro and in vivo systems are well established. However, whether its metabolites do have such beneficial effects like nobiletin remains to be examined. Here we, for the first time, report that 2-(4-hydroxy-3-methoxyphenyl)-5,6,7,8-tetramethoxychromen-4-one (4'-demethylnobiletin), a major metabolite of nobiletin identified in the urine of rats and mice, stimulates the phosphorylation of ERK and CREB and enhances CRE-mediated transcription by activating a PKA/MEK/ERK pathway, like nobiletin, in cultured hippocampal neurons. Since NMDA receptor-mediated ERK signaling is involved in memory processing, including associative memories, we also examined whether 4'-demethylnobiletin, by activating ERK signaling, could restore learning impairment. Chronic intraperitoneal (ip) treatment of the mice with 10 or 50 mg of 4'-demethylnobiletin/kg rescued the NMDA receptor antagonist MK-801-induced learning impairment, accompanied by improvement of the MK-801-induced decrease in the level of ERK phosphorylation in the hippocampus of the animals. Consistently, 4'-demethylnobiletin also restored MK-801-induced inhibition of NMDA-stimulated phosphorylation of not only ERK but also PKA substrates in cultured rat hippocampal neurons. Moreover, we actually detected 4'-demethylnobiletin in the brain of mice following acute ip administration, demonstrating that the metabolite can cross the blood-brain barrier to reach the brain and thereby exert its effects to reverse learning impairment. Therefore, these results suggest that 4'-demethylnobiletin, a bioactive metabolite of nobiletin, may serve as a potential therapeutic agent, at least, for memory disorders associated with a dysregulated NMDA receptor ERK signaling, like nobiletin.
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PMID:4'-Demethylnobiletin, a bioactive metabolite of nobiletin enhancing PKA/ERK/CREB signaling, rescues learning impairment associated with NMDA receptor antagonism via stimulation of the ERK cascade. 1960 43

Adenosine receptors modulate neuronal and synaptic function in a range of ways that may make them relevant to the occurrence, development and treatment of brain ischemic damage and degenerative disorders. A(1) adenosine receptors tend to suppress neural activity by a predominantly presynaptic action, while A(2A) adenosine receptors are more likely to promote transmitter release and postsynaptic depolarization. A variety of interactions have also been described in which adenosine A(1) or A(2) adenosine receptors can modify cellular responses to conventional neurotransmitters or receptor agonists such as glutamate, NMDA, nitric oxide and P2 purine receptors. Part of the role of adenosine receptors seems to be in the regulation of inflammatory processes that often occur in the aftermath of a major insult or disease process. All of the adenosine receptors can modulate the release of cytokines such as interleukins and tumor necrosis factor-alpha from immune-competent leukocytes and glia. When examined directly as modifiers of brain damage, A(1) adenosine receptor (AR) agonists, A(2A)AR agonists and antagonists, as well as A(3)AR antagonists, can protect against a range of insults, both in vitro and in vivo. Intriguingly, acute and chronic treatments with these ligands can often produce diametrically opposite effects on damage outcome, probably resulting from adaptational changes in receptor number or properties. In some cases molecular approaches have identified the involvement of ERK and GSK-3beta pathways in the protection from damage. Much evidence argues for a role of adenosine receptors in neurological disease. Receptor densities are altered in patients with Alzheimer's disease, while many studies have demonstrated effects of adenosine and its antagonists on synaptic plasticity in vitro, or on learning adequacy in vivo. The combined effects of adenosine on neuronal viability and inflammatory processes have also led to considerations of their roles in Lesch-Nyhan syndrome, Creutzfeldt-Jakob disease, Huntington's disease and multiple sclerosis, as well as the brain damage associated with stroke. In addition to the potential pathological relevance of adenosine receptors, there are earnest attempts in progress to generate ligands that will target adenosine receptors as therapeutic agents to treat some of these disorders.
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PMID:Adenosine receptors and neurological disease: neuroprotection and neurodegeneration. 1963 93


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