Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both genetic and pharmacological studies demonstrated that contextual fear conditioning is critically regulated by cyclic AMP-dependent protein kinase (PKA). Since PKA is a broad range protein kinase, a mechanism for confining its activity is required. It has been shown that intracellular spatial compartmentalization of PKA signaling is mediated by A-kinase anchoring proteins (AKAPs). Here, we investigated the role of PKA anchoring to AKAPs in different stages of the memory process (acquisition, consolidation, retrieval and extinction) using contextual fear conditioning, a hippocampus-dependent learning task. Mice were injected intracerebroventricularly or intrahippocampally with the membrane permeable PKA anchoring disrupting peptides St-Ht31 or St-superAKAP-IS at different time points during the memory process. Blocking PKA anchoring to AKAPs resulted in an impairment of fear memory consolidation. Moreover, disrupted PKA anchoring promoted contextual fear extinction in the mouse hippocampus. We conclude that the temporal and spatial compartmentalization of hippocampal PKA signaling pathways, as achieved by anchoring of PKA to AKAPs, is specifically instrumental in long-term contextual fear memory consolidation and extinction, but not in acquisition and retrieval.
Neurobiol Learn Mem 2008 Jul
PMID:Inhibition of PKA anchoring to A-kinase anchoring proteins impairs consolidation and facilitates extinction of contextual fear memories. 1844 35

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

cAMP is a critical second messenger implicated in synaptic plasticity and memory in the mammalian brain. Substantial evidence links increases in intracellular cAMP to activation of cAMP-dependent protein kinase (PKA) and subsequent phosphorylation of downstream effectors (transcription factors, receptors, protein kinases) necessary for long-term potentiation (LTP) of synaptic strength. However, cAMP may also initiate signaling via a guanine nucleotide exchange protein directly activated by cAMP (Epac). The role of Epac in hippocampal synaptic plasticity is unknown. We found that in area CA1 of mouse hippocampal slices, activation of Epac enhances maintenance of LTP without affecting basal synaptic transmission. The persistence of this form of LTP requires extracellular signal-regulated protein kinase (ERK) and new protein synthesis, but not transcription. Because ERK is involved in translational control of long-lasting plasticity and memory, our data suggest that Epac is a crucial link between cAMP and ERK during some forms of protein synthesis-dependent LTP. Activation of Epac represents a novel signaling pathway for rapid regulation of the stability of enduring forms of LTP and, perhaps, of hippocampus- dependent long-term memories.
Learn Mem 2008 Jun
PMID:Activation of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the hippocampus. 1850 14

In the present study the effects of sub-chronic rolipram treatment in an object recognition task in 3-month-old male rats were investigated. Rats remember which object they have explored in a previous trial (T1) when they are tested 1 h later (T2). However, when tested 24 h later, they do not remember which object was presented to them in the first trial. Drug treatments may improve discrimination performance after 24 h, i.e., improve memory for the familiar object. Rats were sub-chronically treated with 0.5 mg/kg rolipram (p.o.) for five consecutive days and tested with a 24 h delay between T1 and T2. Memory performance in the object recognition task was assessed before, during and after sub-chronic treatment. In addition, we investigated whether the timing of the final dose, i.e., 24, 1, or 6 h before training, had an effect on memory performance. During sub-chronic treatment, i.e., after 2-3 days of rolipram treatment, moderate effects on memory performance were observed. Regardless of when the final administration was given, sub-chronic rolipram treatment improved long-term memory performance. Since plasma and brain rolipram levels were undetectable at 24 h before the test, and acute treatment with rolipram 24 h before training had no effects, the observed memory enhancement cannot be attributed to acute rolipram effects. The long-term memory enhancing effects of rolipram might be explained by long-lasting neuronal changes by the chronic treatment due to recurring activation of the cAMP/PKA/CREB pathway leading to CREB phosphorylation.
Neurobiol Learn Mem 2008 Oct
PMID:Sub-chronic rolipram treatment leads to a persistent improvement in long-term object memory in rats. 1855 3

The cAMP-dependent protein kinase (PKA) is known to play a critical role in both transcription-independent short-term or intermediate-term memory and transcription-dependent long-term memory (LTM). Although distinct phases of LTM already have been demonstrated in some systems, it is not known whether these phases require distinct temporal patterns of learning-induced PKA activation. This question was addressed in a robust form of associative LTM that emerges within a matter of hours after single-trial food-reward classical conditioning in the pond snail Lymnaea stagnalis. After establishing the molecular and functional identity of the PKA catalytic subunit in the Lymnaea nervous system, we used a combination of PKA activity measurement and inhibition techniques to investigate its role in LTM in intact animals. PKA activity in ganglia involved in single-trial learning showed a short latency but prolonged increase after classical conditioning. However, while increased PKA activity immediately after training (0-10 min) was essential for an early phase of LTM (6 h), the late phase of LTM (24 h) required a prolonged increase in PKA activity. These observations indicate mechanistically different roles for PKA in recent and more remote phases of LTM, which may underpin different cellular and molecular mechanisms required for these phases.
Learn Mem 2008 Sep
PMID:Different phases of long-term memory require distinct temporal patterns of PKA activity after single-trial classical conditioning. 1877 58

Recent studies have shown that nitric oxide (NO) signaling plays a crucial role in memory consolidation of Pavlovian fear conditioning and in synaptic plasticity in the lateral amygdala (LA). In the present experiments, we examined the role of the cGMP-dependent protein kinase (PKG), a downstream effector of NO, in fear memory consolidation and long-term potentiation (LTP) at thalamic and cortical input pathways to the LA. In behavioral experiments, rats given intra-LA infusions of either the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibited dose-dependent impairments or enhancements of fear memory consolidation, respectively. In slice electrophysiology experiments, bath application of Rp-8-Br-PET-cGMPS or the guanylyl cyclase inhibitor LY83583 impaired LTP at thalamic, but not cortical inputs to the LA, while bath application of 8-Br-cGMP or the guanylyl cyclase activator YC-1 resulted in enhanced LTP at thalamic inputs to the LA. Interestingly, YC-1-induced enhancement of LTP in the LA was reversed by concurrent application of the MEK inhibitor U0126, suggesting that the NO-cGMP-PKG signaling pathway may promote synaptic plasticity and fear memory formation in the LA, in part by activating the ERK/MAPK signaling cascade. As a test of this hypothesis, we next showed that rats given intra-LA infusion of the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibit impaired or enhanced activation, respectively, of ERK/MAPK in the LA after fear conditioning. Collectively, our findings suggest that an NO-cGMP-PKG-dependent form of synaptic plasticity at thalamic input synapses to the LA may underlie memory consolidation of Pavlovian fear conditioning, in part, via activation of the ERK/MAPK signaling cascade.
Learn Mem 2008 Oct
PMID:The NO-cGMP-PKG signaling pathway regulates synaptic plasticity and fear memory consolidation in the lateral amygdala via activation of ERK/MAP kinase. 1883 66

We report here that ZIP, a selective inhibitor of the atypical protein kinase C isoform PKMzeta, abolishes very long-term conditioned taste aversion (CTA) associations in the insular cortex of the behaving rat, at least 3 mo after encoding. The effect of ZIP is not replicated by a general serine/threonine protein kinase inhibitor that is relatively ineffective toward PKMzeta, is independent of the intensity of training and the perceptual quality of the taste saccharin (conditioned stimulus, CS), and does not affect the ability of the insular cortex to re-encode the same specific CTA association again. The memory trace is, however, insensitive to ZIP during or immediately after training. This implies that the experience-dependent cellular plasticity mechanism targeted by ZIP is established following a brief time window after encoding, consistent with the standard period of cellular consolidation, but then, once established, does not consolidate further to gain immunity to the amnesic agent. Hence, we conclude that PKMzeta is not involved in short-term CTA memory, but is a critical component of the cortical machinery that stores long- and very long-term CTA memories.
Learn Mem 2009 Feb
PMID:Boundary conditions for the maintenance of memory by PKMzeta in neocortex. 1918 18

Synaptic facilitation and post-tetanic potentiation (PTP) are believed to necessitate active regeneration of the release machinery and supply of synaptic vesicles to a ready-releasable site. The prevailing hypothesis assumes that synapsins play pivotal roles in these processes. Using a cholinergic synapse formed between cultured Aplysia neurons (B2 and MCn), we demonstrate here that the calcium-activated protease-calpain serves as a major regulating element in the cascade that links electrical activity, elevation of the free intracellular calcium concentration, and short-term synaptic enhancements such as facilitation and PTP. Our study revealed that calpain inhibitors (calpeptin and MG132) transform a facilitating synapse into a depressing one, and reduce its PTP by 80.6%. Inhibition of CaM kinases, PKA, and MAPK also reduced PTP at this synapse. When inhibitors of these kinases were applied together with calpeptin, tetanic stimuli led to synaptic depression. We concluded that at this synapse facilitation and PTP are mediated mainly by the calpain-dependent processes and to a smaller extent by the CaMKs/PKA/MAPK-dependent cascades.
Learn Mem 2009 Feb
PMID:Activity-dependent calpain activation plays a critical role in synaptic facilitation and post-tetanic potentiation. 1918 19

Activity-dependent changes in synaptic strength such as long-term potentiation (LTP) and long-term depression (LTD) are considered to be cellular mechanisms underlying learning and memory. Strengthening of a synapse for a few seconds or minutes is termed short-term potentiation (STP) and is normally unable to take part in the processes of synaptic tagging/capture due to its inability to set the "synaptic tags." Here, we report that priming of synapses with ryanodine receptor agonists such as ryanodine (10 microM) or caffeine (10 mM) facilitates subsequent synaptic tagging/capture, enabling an STP protocol to establish a late-LTP in response to strong tetanization of a heterosynaptic input. We identified calcium/calmodulin-dependent protein kinase II (CaMKII) as mediating the primed synaptic tag setting, which persisted for 1 h. We also identified protein kinase Mzeta (PKMzeta), presumably captured from the strongly tetanized heterosynaptic input, as a plasticity-related protein maintaining the LTP at the tagged synapses. In addition, synaptic tags in primed STP were erased or interfered with by delivering low-frequency depotentiating stimulation 5 or 10 min after its induction, thus preventing capture of newly synthesized proteins. These data reveal a novel form of metaplasticity, whereby ryanodine receptor activation lowers the threshold for subsequent synaptic tagging/capture, thus priming weakly activated synapses for heterosynaptic interactions that promote long-term functional plasticity.
Learn Mem 2009 Mar
PMID:Priming of short-term potentiation and synaptic tagging/capture mechanisms by ryanodine receptor activation in rat hippocampal CA1. 1922 1

It is well established that cAMP signaling within neurons plays a major role in the formation of long-term memories--signaling thought to proceed through protein kinase A (PKA). However, here we show that exchange protein activated by cAMP (Epac) is able to enhance the formation of long-term memory in the hippocampus and appears to do so independent of PKA, thus demonstrating the importance of Epac-mediated signaling in memory consolidation.
Learn Mem 2009 Jun
PMID:Exchange protein activated by cAMP enhances long-term memory formation independent of protein kinase A. 1947 Jun 52


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