Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The members of the mitogen-activated protein (MAP) kinase family -- p44/p42 MAP kinase (ERK), c-jun N-terminal kinase (JNK) and p38 MAP kinase (p38) are known to be important mediators of the physiological plasticity or neurotoxicity induced in the striatum by activation of ionotropic glutamate receptors. However, our knowledge of the class of glutamate receptor and the intracellular pathways involved derives totally from studies on embryonic neurons, where the mechanisms are likely to be totally different from those operating in mature neurons. In superfused striatal slices from adult rats, NMDA and kainate, but not AMPA, were found to activate ERK. No activation of p38 or JNK was detected following treatment with any ionotropic glutamate receptor agonist. The activation of ERK by kainate was blocked by the ERK kinase (MEK) inhibitor PD98059, and the PI3 kinase inhibitor wortmannin, but not by the p38 MAP kinase inhibitor SB203580. This provides evidence for a novel pathway linking striatal kainate receptors to ERK activation via PI3 kinase and MEK.
 ...
PMID:Activation of p44/p42 MAP kinase in striatal neurons via kainate receptors and PI3 kinase. 1131 83

The effects of a novel AMPA receptor potentiator (LY392098) on the expression of brain-derived neurotrophic factor (BDNF) were examined in primary neuron culture. The addition of either AMPA or LY392098 to cortical neurons elicited a time and concentration dependent increase in mRNA encoding BDNF. Moreover, co-addition of subeffective concentrations of AMPA (1 microM) and LY392098 (1 microM) resulted in dramatic increases in both BDNF mRNA (>25-fold) and protein ( approximately 7-fold) levels, whilst no changes in either NT-3 or NT-4 mRNA were detected. More modest ( approximately 1.5-2.5-fold) elevations in BDNF mRNA and protein expression were also produced by combinations of AMPA and LY392098 in cerebellar granule cell neurons. In contrast, AMPA and LY392098, either alone or in combination, did not elevate BDNF mRNA levels in primary astroglial cultures. Maximum elevations in BDNF mRNA and protein were produced by 6-12h of AMPA receptor activation 1-3h of AMPA receptor activation were required to elevate BDNF mRNA levels. AMPA receptor-mediated increases in BDNF mRNA and protein were abolished by the AMPA antagonist, NBQX, but were unaffected by the NMDA antagonist, MK-801. In cortical neuron cultures, activation of both L-type Ca(+2) channels and mitogen-activated protein (MAP) kinases contribute to AMPA receptor-mediated increases in BDNF mRNA. The ability of LY392098 to increase the expression of BDNF in primary neuron culture indicates this and related biarylpropylsulfonamides may be useful in the treatment of neuropsychiatric disorders.
 ...
PMID:Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor potentiator. 1140 93

Because multiple molecular signal transduction pathways regulate cerebellar long-term depression (LTD), which is thought to be a possible molecular and cellular basis of cerebellar learning, the systematic relationship between cerebellar LTD and the currently known signal transduction pathways remains obscure. To address this issue, we built a new diagram of signal transduction pathways and developed a computational model of kinetic simulation for the phosphorylation of AMPA receptors, known as a key step for expressing cerebellar LTD. The phosphorylation of AMPA receptors in this model consists of an initial phase and an intermediate phase. We show that the initial phase is mediated by the activation of linear cascades of protein kinase C (PKC), whereas the intermediate phase is mediated by a mitogen-activated protein (MAP) kinase-dependent positive feedback loop pathway that is responsible for the transition from the transient phosphorylation of the AMPA receptors to the stable phosphorylation of the AMPA receptors. These phases are dually regulated by the PKC and protein phosphatase pathways. Both phases also require nitric oxide (NO), although NO per se does not show any ability to induce LTD; this is consistent with a permissive role as reported experimentally (Lev-Ram et al., 1997). Therefore, the kinetic simulation is a powerful tool for understanding and exploring the behaviors of complex signal transduction pathways involved in cerebellar LTD.
 ...
PMID:Exploration of signal transduction pathways in cerebellar long-term depression by kinetic simulation. 1146 41

The transcription factor nuclear factor-kappa-B (NF-kappaB) is now recognised as a key mediator of physiological and pathological plasticity in the central nervous system (CNS), and ionotropic glutamate receptor stimulation potently triggers NF-kappaB activation. This study was designed to identify the mechanisms responsible for the high basal levels of activated NF-kappaB present in neurons in the cerebral cortex. In cultured cortical neurons, the basal levels of activated NF-kappaB were reduced by the glutamate receptor antagonists MK801 and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but were not affected by exposure to a mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor, a p38 MAP kinase inhibitor or a cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibitor. However, activated NF-kappaB levels were reduced by a guanylate cyclase inhibitor, the Src-family tyrosine kinase inhibitor PP1, or the farnesyl transferase inhibitors manumycin and farnesyl transferase (Ftase) inhibitor 1. There was no additive effect when MK801 was applied together with manumycin. These results suggest that the basal levels of activated NF-kappaB in cortical neurons are maintained partially by synaptic activity involving N-methyl- D-aspartate (NMDA) and AMPA/kainate glutamate receptors, coupled to activation of an Src-family tyrosine kinase and a p21(Ras)-like guanosine triphosphatase (GTPase) in a cGMP-dependent manner. The results are intriguing in the light of the recent identification of a synaptic p21(Ras) activator stimulated by cGMP.
 ...
PMID:Involvement of NMDA receptors and a p21Ras-like guanosine triphosphatase in the constitutive activation of nuclear factor-kappa-B in cortical neurons. 1242 35

Recent pharmacological findings have shown that retrieval of one-trial avoidance learning requires glutamate receptors, cAMP-dependent protein kinase and mitogen-activated protein kinases in the hippocampus, entorhinal, posterior parietal and anterior cingulate cortex. It requires AMPA but not other type of glutamate receptors or the protein kinases in the amygdala. Retrieval is modulated by dopamine D1, beta-noradrenergic, serotonin 1A and cholinergic receptors in the four cortical structures mentioned, and by beta-noradrenergic receptors in the basolateral amygdala. Further, retrieval is also modulated by peripheral ACTH, glucocorticoids, vasopressin, beta-endorphin and catecholamines; these hormones probably act through beta-noradrenergic receptor systems in the basolateral amygdala. Exposure to novelty or the systemic administration of antidepressant drugs prior to retention tests enhances retrieval, even for very remote memories. The effect of novelty is mediated by molecular mechanisms similar to those of retrieval itself.
 ...
PMID:Pharmacological findings contribute to the understanding of the main physiological mechanisms of memory retrieval. 1276 1

The hippocampus produces growth hormone (GH) and contains GH receptors, suggesting a potential role for GH signaling in the regulation of hippocampal function. In agreement with this possibility, previous investigations have found altered hippocampal function and hippocampal-dependent learning and memory after chronic GH administration or deficiency. In this study we applied GH to in vitro rat hippocampal brain slices, to determine whether GH has short-term effects on hippocampal function in addition to previously documented chronic effects. We found that GH enhanced both AMPA- and NMDA-receptor-mediated excitatory postsynaptic potentials (EPSPs) in hippocampal area CA1, but did not alter GABA(A)-receptor-mediated inhibitory synaptic transmission. GH enhancement of excitatory synaptic transmission was gradual, requiring 60-70 min to reach maximum, and occurred without any change in paired-pulse facilitation, suggesting a possible postsynaptic site of action. In CA1 pyramidal neurons, GH enhancement of EPSPs was correlated with significant hyperpolarization and decreased input resistance. GH enhancement of EPSPs required Janus kinase 2 (JAK2), phosphatidylinositol-3 (PI3) kinase, mitogen-activated protein (MAP) kinase kinase (MEK), and synthesis of new proteins. Although PI3 kinase and MEK were required for initiation of GH effects on excitatory synaptic transmission, they were not required for maintained enhancement of EPSPs. GH treatment and tetanus-induced long-term potentiation were mutually occluding, suggesting a common mechanism or mechanisms in both forms of synaptic enhancement. Our results demonstrate that GH has powerful short-term effects on hippocampal function, and extend the timescale for potential roles of GH in regulating hippocampal function and hippocampal-dependent behaviors.
 ...
PMID:Growth hormone enhances excitatory synaptic transmission in area CA1 of rat hippocampus. 1648 59

Although some studies report increased responsiveness of nucleus accumbens (NAc) AMPA receptors (AMPARs) after withdrawal from repeated cocaine treatment, others report decreased responsiveness after withdrawal plus cocaine challenge. Here we examine this apparent contradiction by quantifying cell surface and intracellular AMPAR subunits in the NAc before and after a challenge injection in behaviorally sensitized rats. Because MAPKs (mitogen-activated protein kinases) regulate AMPAR trafficking and are implicated in addiction, we also evaluated phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. Glutamate receptor 1 (GluR1) and GluR2 surface/intracellular (S/I) ratios were increased after 14 d of withdrawal in sensitized rats but were decreased 24 h after challenge with cocaine (which elicited a sensitized locomotor response) or saline (which elicited conditioned locomotion). These findings suggested redistribution of GluR1/2-containing receptors, a possibility supported by immunoprecipitation experiments indicating that most AMPARs in the NAc are GluR1/2 or GluR2/3, with few homomeric GluR1 or GluR1/3 receptors. In sensitized rats, ERK phosphorylation in the NAc increased during withdrawal and normalized after cocaine challenge. JNK phosphorylation also increased after withdrawal, but after cocaine challenge, it was inversely related to GluR1 and GluR2 S/I ratios. After saline challenge, p38 phosphorylation was increased. In summary, surface expression of GluR1/2-containing AMPARs increased in the NAc of sensitized rats, but AMPARs internalized after a single reexposure to cocaine or cocaine-related cues. ERK phosphorylation paralleled AMPAR surface expression. Although JNK results were complex, JNK and p38 may be involved in AMPAR internalization after cocaine or saline challenge, respectively.
 ...
PMID:Cell surface AMPA receptors in the rat nucleus accumbens increase during cocaine withdrawal but internalize after cocaine challenge in association with altered activation of mitogen-activated protein kinases. 1835

Monoaminergic-based drugs remain the primary focus of pharmaceutical industry drug discovery efforts for mood disorders, despite serious limitations regarding their ability to achieve remission. The quest for novel therapies for unipolar depression and bipolar disorder has generally centered on two complementary approaches: (1) understanding the presumed therapeutically relevant biochemical targets of currently available medications, and using that knowledge to design new drugs directed at both direct biochemical targets and downstream targets that are regulated by chronic drug administration; and (2) developing pathophysiological models of the illness to design therapeutics to attenuate or prevent those pathological processes. This review describes several promising drugs and drug targets for mood disorders using one or both of these approaches. Agents interacting with non-catecholamine neurotransmitter systems with particular promise for unipolar and bipolar depression include excitatory amino acid neurotransmitter modulators (eg, riluzole, N-methyl-D-aspartate antagonists, and AMPA receptor potentiators) and neuropeptide antagonists (targeting corticotropin releasing factor-1 and neurokinin receptors). Potential antidepressant and mood-stabilizing agents targeting common intracellular pathways of known monoaminergic agents and lithium/mood stabilizers are also reviewed, such as neurotrophic factors, extracellular receptor-coupled kinase (ERK) mitogen-activated protein (MAP) kinase and the bcl-2 family of proteins, and inhibitors of phosphodiesterase, glycogen synthase kinase-3, and protein kinase C. A major thrust of drug discovery in mood disorders will continue efforts to identify agents with rapid and sustained onsets of action (such as intravenous administration of ketamine), as well as identify drugs used routinely in non-psychiatric diseases for their antidepressant and mood-stabilizing properties.
 ...
PMID:Novel drugs and therapeutic targets for severe mood disorders. 1817 33

There is increasing evidence that severe mood disorders are associated with impairment of structural plasticity and cellular resilience. Cumulative data demonstrate that mood stabilizers regulate intracellular signaling cascades, including protein kinase C (PKC), PKA, mitogen-activated protein (MAP) kinase, glycogen synthase kinase 3-beta (GSK3-beta) and intracellular calcium, which are signaling pathways that regulate synaptic plasticity. In this context, it is noteworthy that a growing body of data indicates that the glutamatergic system, has a major role in neuronal plasticity and cellular resilience, might be involved in the pathophysiology and treatment of mood disorders. AMPA glutamate-receptor trafficking is important in synaptic plasticity and might play crucial roles in maintaining critical neuronal circuits associated with mood. Two clinically effective, structurally dissimilar, antimanic agents, lithium and valproate (VPA), down-regulate synaptic expression of AMPA receptor subunit GluR1 in hippocampus in chronically treated rats. This reduction in synaptic GluR1 by lithium and VPA is due to attenuated phosphorylation of GluR1 at a specific PKA site (residue 845 of GluR1), which is crucial for AMPA receptor insertion. By contrast,imipramine, which can provoke mania, increases synaptic expression of GluR1 in the hippocampus in vivo. Furthermore, there is ample evidence from preclinical and clinical research that the glutamatergic system is involved in the pathophysiology of mood disorders and that many of the somatic treatments used for mood disorders including antidepressants, mood stabilizers, atypical antipsychotic drugs and electroconvulsive therapy have both direct and indirect effects on the glutamatergic system. Given these findings, further research with medications that specifically affect the glutamatergic system is warranted. Recent studies in our lab have shown that riluzole, a FDA approved medicine that regulates the glutamatergic system, shows antidepressant efficacy in unipolar and bipolar depression. These studies indicate that regulation of glutamate-mediated synaptic plasticity might play a role in the treatment of mood disorders, and raise new avenues for novel therapies for this devastating illness.
 ...
PMID:Bipolar disorder: involvement of signaling cascades and AMPA receptor trafficking at synapses. 1863

Although it is well established that AMPA receptor (AMPAR) trafficking is a central event in several forms of synaptic plasticity, the mechanisms that regulate the surface expression of AMPARs are poorly understood. Previous work has shown that striatal-enriched protein tyrosine phosphatase (STEP) mediates NMDAR endocytosis. This protein tyrosine phosphatase is enriched in the synapses of the striatum, hippocampus, cerebral cortex, and other brain regions. In the present investigation, we have explored whether STEP also regulates AMPAR internalization. We found that (RS)-3,5-dihydroxyphenylglycine (DHPG) stimulation triggered a dose-dependent increase in STEP translation in hippocampal slices and synaptoneurosomes, a process that requires stimulation of mGluR5 (metabotropic glutamate receptor 5) and activation of mitogen-activated protein kinases and phosphoinositide-3 kinase pathways. DHPG-induced AMPAR internalization and tyrosine dephosphorylation of GluR2 (glutamate receptor 2) was blocked by a substrate-trapping TAT-STEP [C/S] protein in hippocampal slices and cultures. Moreover, DHPG-triggered AMPAR internalization was abolished in STEP knock-out mice and restored after replacement of wild-type STEP. These results suggest a role for STEP in the regulation of AMPAR trafficking.
 ...
PMID:The tyrosine phosphatase STEP mediates AMPA receptor endocytosis after metabotropic glutamate receptor stimulation. 1892 32


1 2 Next >>