Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitogen-activated protein kinase (MAPK) is abundantly expressed in postmitotic neurons of the developed nervous system. MAPK is activated and required for induction of long-term potentiation (LTP) in the CA1 area of the hippocampus, which is blocked by the specific inhibitor of the MAPK kinase, PD 098059. Recently it was demonstrated that MAPK is activated in the hippocampus after training and is necessary for contextual fear conditioning learning. The present work tests the role of the MAPK cascade in step-down inhibitory avoidance (IA) retention. PD 098059 (50 microM) was bilaterally injected (0.5 microl/side) into the CA1 region of the dorsal hippocampus or entorhinal cortex at 0, 90, 180, or 360 min, or into the amygdala or parietal cortex at 0, 180, or 360 min after IA training in rats using a 0.4-mA foot shock. Retention testing was carried out 24 h after training. PD 098059 impaired retention when injected into the dorsal hippocampus at 180 min, but not 0, 90, and 360 min after training. When infused into the entorhinal cortex, PD 098059 was amnestic at 0 and 180 min, but not at 90 and 360 min after training. The MAPKK inhibitor also impairs IA retention when infused into the parietal cortex immediately after training, but not at 180 or 360 min. Infusions performed into amygdala were amnestic at 180 min, but not at 0 and 360 min after training. Our results suggest a time-dependent involvement of the MAPK cascade in the posttraining memory processing of IA; the time dependency is different in the hippocampus, amygdala, entorhinal cortex, or parietal cortex of rats.
Neurobiol Learn Mem 2000 Jan
PMID:Time-dependent impairment of inhibitory avoidance retention in rats by posttraining infusion of a mitogen-activated protein kinase kinase inhibitor into cortical and limbic structures. 1068 20

Rats were implanted with cannulae in the CA1 area of the dorsal hippocampus or in the entorhinal cortex and trained in one-trial step-down inhibitory avoidance. Two retention tests were carried out in each animal, one at 1.5 h to measure short-term memory (STM) and another at 24 h to measure long-term memory (LTM). The purpose of the present study was to screen the effect on STM of various drugs previously shown to affect LTM of this task when given posttraining at the same doses that were used here. The drugs and doses were the guanylyl cyclase inhibitor LY83583 (LY, 2.5 microMg), the inhibitor of Tyr-protein kinase at low concentrations and of protein kinase G (PKG) at higher concentrations lavendustin A (LAV, 0.1 and 0.5 microMg), the PKG inhibitor KT5823 (2.0 microMg), the protein kinase C (PKC) inhibitor staurosporin (STAU, 2.5 microMg), the inhibitor of calcium/ calmodulin protein kinase II (CaMKII) KN62 (3.6 microMg), the protein kinase A (PKA) inhibitor KT5720 (0.5 microMg), and the mitogen-activated protein kinase kinase (MAPKK) inhibitor PD098059 (PD, 0.05 microMg). PD was dissolved in saline; all the other drugs were dissolved in 20% dimethyl sulfoxide. In all cases the drugs affected LTM as had been described in previous papers. The drugs affected STM and LTM differentially depending on the brain structure into which they were infused. STM was inhibited by KT5720, LY, and PD given into CA1 and by STAU and KT5720 given into the entorhinal cortex. PD given into the entorhinal cortex enhanced STM. LTM was inhibited by STAU, KN62, KT5720, KT5823, and LAV (0.5 microMg) given into CA1 and by STAU, KT5720, and PD given into the entorhinal cortex. The results suggest that STM and LTM involve different physiological mechanisms but are to an extent linked. STM appears to require PKA, guanylyl cyclase, and MAPKK activity in CA1 and PKA and PKC activity in the entorhinal cortex; MAPKK seems to play an inhibitory role in STM in the entorhinal cortex. In contrast, LTM appears to require PKA and PKC activity in both structures, guanylyl cyclase, PKG, and CaMKII activity in CA1, and MAPKK activity in the entorhinal cortex.
Neurobiol Learn Mem 2000 Mar
PMID:Short- and long-term memory are differentially affected by metabolic inhibitors given into hippocampus and entorhinal cortex. 1070 24

Long-term habituation to a novel environment is one of the most elementary forms of nonassociative learning. Here we studied the effect of pre- or posttraining intrahippocampal administration of drugs acting on specific molecular targets on the retention of habituation to a 5-min exposure to an open field measured 24 h later. We also determined whether the exposure to a novel environment resulted in the activation of the same intracellular signaling cascades previously shown to be activated during hippocampal-dependent associative learning. The immediate posttraining bilateral infusion of CNQX (1 microg/side), an AMPA/kainate glutamate receptor antagonist, or of muscimol (0.03 microg/side), a GABA(A) receptor agonist, into the CA1 region of the dorsal hippocampus impaired long-term memory of habituation. The NMDA receptor antagonist AP5 (5 microg/side) impaired habituation when infused 15 min before, but not when infused immediately after, the 5-min training session. In addition, KN-62 (3.6 ng/side), an inhibitor of calcium calmodulin-dependent protein kinase II (CaMKII), was amnesic when infused 15 min before or immediately and 3 h after training. In contrast, the cAMP-dependent protein kinase (PKA) inhibitor Rp-cAMPS, the mitogen-activated protein kinase kinase (MAPKK) inhibitor PD098059, and the protein synthesis inhibitor anisomycin, at doses that fully block memory formation of inhibitory avoidance learning, did not affect habituation to a novel environment. The detection of spatial novelty is associated with a sequential activation of PKA, ERKs (p44 and p42 MAPKs) and CaMKII and the phosphorylation of c-AMP responsive element-binding protein (CREB) in the hippocampus. These findings suggest that memory formation of spatial habituation depends on the functional integrity of NMDA and AMPA/kainate receptors and CaMKII activity in the CA1 region of the hippocampus and that the detection of spatial novelty is accompanied by the activation of at least three different hippocampal protein kinase signaling cascades.
Learn Mem
PMID:Role of hippocampal signaling pathways in long-term memory formation of a nonassociative learning task in the rat. 1104 Feb 65

Lesion studies have provided evidence that the entorhinal cortex (EC) participates in spatial memory. However, the molecular cascades that underlie memory-associated changes in the EC and its specific role in spatial memory, however, have not been clearly delineated. Recently, it has been shown that activation of extracellular signal-regulated kinase (Erk, a mitogen-activated protein kinase family member) in the dorsal hippocampus is necessary for spatial memory. To examine whether similar mechanisms are used for spatial memory storage in the EC, Erk activity was inhibited after training in the Morris water maze. Bilateral infusion of the mitogen-activated protein kinase kinase inhibitor PD098059 into the EC immediately after training resulted in a memory deficit observed during a retention test performed 48 h later. This deficit was abolished with pretraining in a different water maze in which animals were able to learn the general task requirements and the appropriate search strategies. The absence of a deficit indicates that Erk activity in the EC may be involved in storing the task requirements or the search strategies. The findings presented in this article are consistent with the idea that the EC is involved in spatial memory and indicate that Erk activity is necessary for memory consolidation in this structure.
Learn Mem
PMID:Extracellular signal-regulated kinase activity in the entorhinal cortex is necessary for long-term spatial memory. 1217 29

Brain-derived neurotrophic factor (BDNF) is a potent modulator of synaptic transmission and plasticity in the CNS, acting both pre- and postsynaptically. We demonstrated recently that BDNF/TrkB signaling increases dendritic spine density in hippocampal CA1 pyramidal neurons. Here, we tested whether activation of the prominent ERK (MAPK) signaling pathway was responsible for BDNF's effects on spine growth. Slice cultures were transfected with enhanced yellow fluorescent protein (eYFP) by particle-mediated gene transfer, and CA1 pyramidal neurons were imaged by laser-scanning confocal microscopy. We confirmed that BDNF (24 h) increases spine density in apical dendrites of CA1 neurons. The MEK (ERK kinase) inhibitors PD98059 and U0126 completely prevented the increase in spine density induced by BDNF, without having an effect on spine density by themselves. In contrast to its actions on cortical pyramidal neurons, BDNF had minor and rather localized effects on dendritic complexity in hippocampal pyramidal neurons, increasing the total length, but not the branching of apical dendrites within CA1 stratum radiatum, without affecting basal dendrites in stratum oriens. Our results support the hypothesis that the ERK-signaling pathway not only mediates long-term synaptic plasticity and hippocampal-dependent learning, but it is also involved in the structural remodeling of excitatory spine synapses triggered by neurotrophins.
Learn Mem
PMID:ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. 1505 32

In this study, we analyzed the participation of the entorhinal cortex in extinction of a learned aversive response. Rats with infusion cannulae aimed to the entorhinal cortex were trained in a one-trial step-down inhibitory avoidance task (IA) and submitted to four consecutive daily test sessions without the footshock, a procedure that induced extinction of the conditioned response in control animals. When infused into the entorhinal cortex immediately after the first extinction session at doses able to block consolidation of IA memory, the NMDA receptor antagonist, AP5 (25 nmol/side), the inhibitor of protein synthesis anisomycin (300 nmol/side) and the inhibitor of CaMKII, KN-93 (10 nmol/side), but not the MEK1/2 inhibitor PD-98059 (5 nmol/side) hindered extinction of the IA response. The same results were obtained when the interval between the first and second test session was 48 instead of 24h. The data indicate that normal functionality of the NMDA receptors, together with CaMKII activity and protein synthesis are necessary in the entorhinal cortex at the time of the first test session to generate extinction. Our results also suggest that the ERK1/2 pathway does not play a role in this process.
Neurobiol Learn Mem 2006 Mar
PMID:The entorhinal cortex plays a role in extinction. 1629 Jan 95

Recent studies have shown that consolidated fear memories, when reactivated, return to a labile state that requires a new protein synthesis for reconsolidation. Post-retrieval infusion of an inhibitor of protein synthesis blocks memory reconsolidation processes. In a previous research, the role of MAPKs in memory consolidation has been shown in emotional tasks, such as passive and active avoidance. In particular, mice knockout for ERK1 had a better performance in comparison to wild type mice in both passive and active avoidance tasks. In the present study, in order to investigate the involvement of MAPKs in memory reconsolidation processes we administered immediately after retrieval, different doses of SL327 (an inhibitor of MEK, a kinase that activates both ERK1 and ERK2) both in C57BL/6 (C57) mice and ERK1 mutant mice tested in a fear conditioning task. Systemic administration of SL327 dose-dependently reduced the memory reconsolidation of fear memories in C57 mice. Moreover, SL327 administration impaired memory reconsolidation also in ERK1 mutant mice. Altogether, these results clearly indicate a central role for ERK2 protein in memory reconsolidation processes in mice.
Neurobiol Learn Mem 2006 Sep
PMID:A role for ERK2 in reconsolidation of fear memories in mice. 1650 49

Fear conditioning is a popular model for investigating physiological and cellular mechanisms of memory formation. In this paradigm, a footshock is either systematically associated to a tone (paired conditioning) or is pseudorandomly distributed (unpaired conditioning). In the former procedure, the tone/shock association is acquired, whereas in the latter procedure, the context/shock association will prevail. Animals with chronically implanted recording electrodes show enhanced amplitude of the extracellularly recorded field EPSP in CA1 pyramidal cells for up to 24 h after unpaired, but not paired, fear conditioning. This is paralleled by a differential activation of the ERK/CREB pathway in CA1, which is monophasic in paired conditioning (0-15 min post-conditioning), but biphasic (0-1 h and 9-12 h post-conditioning) in unpaired conditioning as revealed by immunocytochemistry and Western blotting. Intrahippocampal injection of the MEK inhibitor U0126 prior to each phase prevents the activation of both ERK1/2 and CREB after unpaired conditioning. Block of any activation phase leads to memory impairment. We finally reveal that the biphasic activation of ERK/CREB activity is independently regulated, yet both phases are critically required for the consolidation of long-term memories following unpaired fear conditioning. These data provide compelling evidence that CA1 serves different forms of memory by expressing differential cellular mechanisms that are dependent on the training regime.
Learn Mem
PMID:Foreground contextual fear memory consolidation requires two independent phases of hippocampal ERK/CREB activation. 1670 40

Long-term memory formation is regulated by many distinct molecular mechanisms that control gene expression. An emerging model for effecting a stable, coordinated pattern of gene transcription involves epigenetic tagging through modifications of histones or DNA. In this study, we investigated the regulation of histone phosphorylation in the hippocampus by the ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway. We found that activation of ERK/MAPK in vitro significantly increased histone H3 phosphorylation in hippocampal area CA1. Furthermore, we found that contextual fear conditioning in vivo leads to a rapid time-dependent increase in histone H3 phosphorylation in area CA1. This increase paralleled the time course of contextual fear-dependent activation of ERK, and was inhibited in vivo by a latent inhibition paradigm as well as by injection of an N-methyl-d-aspartic acid receptor (NMDA-R) antagonist. Finally, injection of an inhibitor of MEK (MAP kinase/ERK kinase), the unique dual-specificity kinase upstream of ERK, blocked the increase in histone H3 phosphorylation seen after contextual fear conditioning. These results demonstrate that changes in histone phosphorylation in the hippocampus are regulated by ERK/MAPK following a behavioral fear conditioning paradigm.
Learn Mem
PMID:ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning. 1674 Dec 77

Drug-associated cues are critical in reinstating the drug taking behavior even during prolonged abstinence and thus are thought to be a key factor to induce drug craving and to cause relapse. Amygdaloid complex has been known for its physiological function in mediating emotional experience storage and emotional cues-regulated memory retrieval. This study was undertaken to examine the role of basolateral nuclei of amygdala and the intracellular signaling molecule in drug cues-elicited cocaine memory retrieval. Systemic anisomycin treatment prior to the retrieval test abolished the cues-provoked cocaine conditioned place preference (CPP) memory. Likewise, a similar blockade of cues-provoked cocaine CPP performance was achieved by infusion of anisomycin and cycloheximide into the basolateral nuclei of amygdala before the test. Intra-amygdaloid infusion of H89, a protein kinase A inhibitor, or U0126, a MEK inhibitor, did not affect retrieval of the cues-elicited cocaine CPP memory. In contrast, intra-amygdaloid infusion of NPC 15437, a PKC inhibitor, abolished the cues-elicited cocaine CPP expression, while left the memory per se intact. Intra-amygdaloid infusion of NPC 15437 did not seem to affect locomotor activity or exert observable aversive effect. Taken together, our results suggest that activation of PKC signaling pathway and probably downstream de novo protein synthesis in the basolateral nuclei of amygdala is required for the cues-elicited cocaine memory performance. However, temporary inhibition of this signaling pathway does not seem to affect cocaine CPP memory per se.
Neurobiol Learn Mem 2008 Jul
PMID:Activation of amygdaloid PKC pathway is necessary for conditioned cues-provoked cocaine memory performance. 1844 36


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