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)

There is substantial evidence that protein kinases, through the phosphorylation of substrate proteins, play a significant role in information processing in the brain, including processes underlying memory formation. Inhibition of the activity of the cyclic-adenosine monophosphate-dependent protein kinase A by the highly specific inhibitor, halofantrine, resulted in impairment of memory formation in day-old chicks trained on a single-trial passive avoidance task. A dose of 9.6 ng/chick halofantrine induced amnesia at the beginning of a protein synthesis-dependent long-term memory stage, the last of three stages of memory postulated to underly memory formation in the chick following passive avoidance learning. The concentration of halofantrine required for 50% inhibition of chick brain protein kinase A was found to be similar to that observed for bovine heart and rat liver. The amnestic effect of halofantrine is tentatively attributed to interference with de novo protein synthesis necessary for long-term memory consolidation. Neither anthraquinone nor the anthraquinone derivative anthraflavic acid, which have little effect on protein kinase A activity, affected memory retention. On the other hand, two other anthraquinone derivatives, chrysophanic acid and purpurin, which inhibit PKA activity, at doses of 0.25 and 0.5 ng/chick also yielded retention deficits. In these cases, however, retention losses occurred earlier than observed with halofantrine, at about 30 min post-training. The earlier effects of these inhibitors may be due to the additional inhibitory action of these compounds on protein kinase C activity, which has been demonstrated in previous studies to be implicated, possibly through phosphorylation of the GAP43 phosphoprotein, in memory processing in the stage of memory immediately preceding the protein synthesis-dependent long-term stage.
Neurobiol Learn Mem 1995 Sep
PMID:Inhibitors of cAMP-dependent protein kinase impair long-term memory formation in day-old chicks. 758 18

Retrograde amnesia was induced in rats trained in step-down inhibitory avoidance by four different treatments: an ip injection of beta-endorphin (1.0 microgram kg), an electroconvulsive shock (ECS), an intrahippocampal infusion of the calcium/calmodulin protein kinase II inhibitor, KN62 (0.08 microgram/side), given 0 h after training, or an intrahippocampal infusion of the protein kinase A inhibitor, KT5720 (0.5 microgram/side), given 3 h after training. Pretest ip injections of ACTH (0.2 microgram/kg) or vasopressin (10.0 micrograms/kg), but not saline, reversed the amnesia caused by beta-endorphin and ECS but not that caused by the enzyme inhibitors. This suggests that the amnesia produced by intrahippocampal KN62 and KT5720 administration is stronger than that caused by ECS and beta-endorphin, possibly because the former interfere directly with specific steps of the core biochemical chain of events that underlies memory consolidation.
Neurobiol Learn Mem 1997 Sep
PMID:Systemic administration of ACTH or vasopressin reverses the amnestic effect of posttraining beta-endorphin or electroconvulsive shock but not that of intrahippocampal infusion of protein kinase inhibitors. 932 61

Recent data have demonstrated a biochemical sequence of events in the rat hippocampus that is necessary for memory formation of inhibitory avoidance behavior. The sequence initially involves the activation of three different types of glutamate receptors followed by changes in second messengers and biochemical cascades led by enhanced activity of protein kinases A, C, and G and calcium-calmodulin protein kinase II, followed by changes in glutamate receptor subunits and binding properties and increased expression of constitutive and inducible transcription factors. The biochemical events are regulated early after training by hormonal and neurohumoral mechanisms related to alertness, anxiety, and stress, and 3-6 h after training by pathways related to mood and affect. The early modulation is mediated locally by GABAergic, cholinergic, and noradrenergic synapses and by putative retrograde synaptic messengers, and extrinsically by the amygdala and possibly the medial septum, which handle emotional components of memories and are direct or indirect sites of action for several hormones and neurotransmitters. The late modulation relies on dopamine D1, beta-noradrenergic, and 5HT1A receptors in the hippocampus and dopaminergic, noradrenergic, and serotoninergic pathways. Evidence indicates that hippocampal activity mediated by glutamate AMPA receptors must persist during at least 3 h after training in order for memories to be consolidated. Probably, this activity is transmitted to other areas, including the source of the dopaminergic, noradrenergic, and serotoninergic pathways, and the entorhinal and posterior parietal cortex. The entorhinal and posterior parietal cortex participate in memory consolidation minutes after the hippocampal chain of events starts, in both cases through glutamate NMDA receptor-mediated processes, and their intervention is necessary in order to complete memory consolidation. The hippocampus, amygdala, entorhinal cortex, and parietal cortex are involved in retrieval in the first few days after training; at 30 days from training only the entorhinal and parietal cortex are involved, and at 60 days only the parietal cortex is necessary for retrieval. Based on observations on other forms of hippocampal plasticity and on memory formation in the chick brain, it is suggested that the hippocampal chain of events that underlies memory formation is linked to long-term storage elsewhere through activity-dependent changes in cell connectivity.
Neurobiol Learn Mem 1997 Nov
PMID:Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures. 939 90

T cell recognition of antigens displayed on the surface of antigen presenting cell results in rapid activation of protein tyrosine kinases and kinase C. This process leads to second messengers, such as inositol phosphates and diacylgycerol, and phosphorylation of multiple proteins. The role of different protein kinases in the activation of peripheral blood mononuclear cells (PBMC) from Schistosoma mansoni infected individuals was evaluated using genistein and H-7, specific inhibitors of protein tyrosine kinase and kinase C, respectively. Our results showed that proliferation in response to soluble egg antigen or adult worm antigen preparation of S. mansoni was reduced when PBMC were cultured in presence of protein kinase inhibitors. Using these inhibitors on in vitro granuloma reaction, we also observed a marked reduction of granuloma index. Taken together, our results suggest that S. mansoni antigen activation of PBMC involves protein kinases activity.
Mem Inst Oswaldo Cruz
PMID:The role of protein kinases in antigen-activation of peripheral blood mononuclear cells of Schistosoma mansoni infected individuals. 956 27

Infusion of the calcium-calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-62 (3.5 ng/side) 0 h after training into rat hippocampus CA1 or amygdala has been known for years to cause retrograde amnesia for step-down inhibitory avoidance. On the other hand, drugs that indirectly stimulate protein kinase A (PKA) (8-Br-cAMP, 1.25 microg/side; norepinephrine, 0.3 microg/side; the dopamine D1 receptor agonist, SKF38393, 7.5 microg/side) infused 3 h posttraining into CA1 but not amygdala markedly facilitate retention of this task. Here we find that 8-Br-cAMP, norepinephrine, or SKF38393 given 3 h posttraining into rat CA1 reverses the amnestic effect of KN-62 given into the amygdala 0 h after training, but not that of KN-62 given into CA1 0 h posttraining. The findings bear on the participation of CaMKII and of the cAMP/PKA cascade in memory processes in the hippocampus and the amygdala. Both cascades have been proposed to play a role in memory: CaMKII in the early phase and PKA in the transition between the early phase and long-term memory. Clearly, in CA1, both cascades are involved and are crucial, and the CaMKII cascade must precede the PKA cascade. In contrast, in the amygdala, only the CaMKII cascade is active, and it does not play a central role in memory, inasmuch as its deleterious effect may be fully recovered by stimulation of the PKA cascade in the hippocampus. This further supports the contention that the hippocampus is essential for memory formation of this task, as it is for many others, whereas the amygdala appears to play instead an early modulatory role.
Neurobiol Learn Mem 1999 Jan
PMID:Stimulators of the cAMP cascade reverse amnesia induced by intra-amygdala but not intrahippocampal KN-62 administration. 988 75

Fear conditioning has received extensive experimental attention. However, little is known about the molecular mechanisms that underlie fear memory consolidation. Previous studies have shown that long-term potentiation (LTP) exists in pathways known to be relevant to fear conditioning and that fear conditioning modifies neural processing in these pathways in a manner similar to LTP induction. The present experiments examined whether inhibition of protein synthesis, PKA, and MAP kinase activity, treatments that block LTP, also interfere with the consolidation of fear conditioning. Rats were injected intraventricularly with Anisomycin (100 or 300 microg), Rp-cAMPS (90 or 180 microg), or PD098059 (1 or 3 microg) prior to conditioning and assessed for retention of contextual and auditory fear memory both within an hour and 24 hr later. Results indicated that injection of these compounds selectively interfered with long-term memory for contextual and auditory fear, while leaving short-term memory intact. Additional control groups indicated that this effect was likely due to impaired memory consolidation rather than to nonspecific effects of the drugs on fear expression. Results suggest that fear conditioning and LTP may share common molecular mechanisms.
Learn Mem
PMID:Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase. 1032 35

Perfusion of hippocampal slices with an inhibitor nitric oxide (NO) synthase blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.
Learn Mem
PMID:On the respective roles of nitric oxide and carbon monoxide in long-term potentiation in the hippocampus. 1048 62

Previous work has shown that mice missing the alpha-isoform of calcium-calmodulin-dependent protein kinase II (alpha-CaMKII) have a deficiency in CA1 hippocampal long-term potentiation (LTP). Follow-up studies on subsequent generations of these mutant mice in a novel inbred background by our laboratories have shown that whereas a deficiency in CA1 LTP is still present in alpha-CaMKII mutant mice, it is different both quantitatively and qualitatively from the deficiency first described. Mice of a mixed 129SvOla/SvJ;BALB/c;C57B1/6 background derived from brother/sister mating of the alpha-CaMKII mutant line through multiple generations (>10) were produced by use of in vitro fertilization. Although LTP at 60 min post-tetanus was clearly deficient in these (-/-) alpha-CaMKII mice (42.6%, n = 33) compared with (+/+) alpha-CaMKII control animals (81.7%, n = 17), alpha-CaMKII mutant mice did show a significant level of LTP. The amount of LTP observed in alpha-CaMKII mutants was normally distributed, blocked by APV (2.7%, n = 8), and did not correlate with age. Although this supports a role for alpha-CaMKII in CA1 LTP, it also suggests that a form of alpha-CaMKII-independent LTP is present in mice that could be dependent on another kinase, such as the beta-isoform of CaMKII. A significant difference in input/output curves was also observed between (-/-) alpha-CaMKII and (+/+) alpha-CaMKII animals, suggesting that differences in synaptic transmission may be contributing to the LTP deficit in mutant mice. However, tetani of increasing frequency (50, 100, and 200 Hz) did not reveal a higher threshold for potentiation in (-/-) alpha-CaMKII mice compared with (+/+) alpha-CaMKII controls.
Learn Mem
PMID:CA1 long-term potentiation is diminished but present in hippocampal slices from alpha-CaMKII mutant mice. 1045 59

We have used a combined genetic and pharmacological approach to define the time course of the requirement for protein kinase A (PKA) and protein synthesis in long-term memory for contextual fear conditioning in mice. The time course of amnesia in transgenic mice that express R(AB) and have genetically reduced PKA activity in the hippocampus parallels that observed both in mice treated with inhibitors of PKA and mice treated with inhibitors of protein synthesis. This PKA- and protein synthesis-dependent memory develops between 1 hr and 3 hr after training. By injecting the protein synthesis inhibitor anisomycin or the PKA inhibitor Rp-cAMPs at various times after training, we find that depending on the nature of training, contextual memory has either one or two brief consolidation periods requiring synthesis of new proteins, and each of these also requires PKA. Weak training shows two time periods of sensitivity to inhibitors of protein synthesis and PKA, whereas stronger training exhibits only one. These studies underscore the parallel dependence of long-term contextual memory on protein synthesis and PKA and suggest that different training protocols may recruit a common signaling pathway in distinct ways.
Learn Mem
PMID:Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. 1045 61

Previous results have suggested that cGMP is involved in hippocampal long-term potentiation (LTP), perhaps as the presynaptic effector of a retrograde messenger. However, other studies have failed to replicate some of those results, making the role of cGMP uncertain. We therefore reexamined this question and identified several variables that can affect the contribution of cGMP. First, brief perfusion with 8-Br-cGMP before weak tetanic stimulation produced long-lasting potentiation in the CA1 region of hippocampal slices, but more prolonged perfusion with 8-Br-cGMP before the tetanus did not produce long-lasting potentiation. Second, the activity-dependent long-lasting potentiation by cGMP analogs was reduced when NMDA receptors were completely blocked, indicating that NMDA receptor activation contributes to, but is not required for, the potentiation. The amount of reduction of the potentiation differed with different protocols, and in some cases could be complete. Third, LTP produced by strong tetanic stimulation in the stratum radiatum of CA1 (which expresses eNOS) was blocked by inhibitors of soluble guanylyl cyclase or cGMP-dependent protein kinase, but LTP in the stratum oriens (which does not express eNOS) was not. The results of these experiments should help to explain some of the discrepant findings from previous studies, and, in addition, may provide insights into the mechanisms and functional role of the cGMP-dependent component of LTP.
Learn Mem
PMID:The specific role of cGMP in hippocampal LTP. 1045 67


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