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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein phosphorylation represents a key process by which neuronal function is regulated by first messengers interacting with extracellular membrane receptors. Protein kinases transfer the phosphate group from ATP to neuron specific proteins and phosphatases, catalyzing the removal of the phosphate group, shut off the signal by restoring the reactive form of the protein. These phosphorylation processes seem to be particularly important in long-term changes which follow sustained activation of neurons. Particular importance has been given to the Calcium/phospholipid-dependent protein kinase (PKC) as the molecular mechanism in synaptic plasticity associated with learning and memory. We have studied the changes of PKC activity in an animal model of impaired cognitive functions as a consequence of an exposure during embryonic life to an antimitotic agent, methylazoxy-methanol acetate (MAM). Treatment at gestational day (GD) 15 results in offspring showing a dose-dependent reduction in the size of cortex and hippocampus. When adult, these animals show impairments in several tests for learning and memory. In hippocampal slice preparations from MAM-treated rats, Long-Term Potentiation could not be induced in the CA1 region, the area affected by the treatment. However, in the hippocampal dentate gyrus, an area not affected by the treatment, LTP could be induced. Moreover, these animals show area-specific changes in the phosphorylation state of the protein B-50/GAP-43, a well characterized neuron specific substrate for PKC. By changing the time of MAM exposure, i.e. at GD19, a different pattern of brain damage occurs and this results both in a different pattern in behavior and B-50 phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synaptic protein phosphorylation changes in animals exposed to neurotoxicants during development. 785 86

Age-related alterations in binding sites of major second messengers and a selective adenosine 3',5'-cyclic monophosphate (cyclic-AMP) phosphodiesterase (PDE) in the gerbil brain were analysed by receptor autoradiography. [3H]Phorbol 12,13-dibutyrate (PDBu), [3H]inositol 1,4,5-trisphosphate (IP3), [3H]forskolin, [3H]cyclic-AMP, and [3H]rolipram were used to label protein kinase C (PKC), IP3 receptor, adenylate cyclase, cyclic-AMP dependent protein kinase (PKA), and Ca2+/calmodulin-independent cyclic-AMP PDE, respectively. In middle-aged gerbils (16 months old), [3H]PDBu binding was significantly reduced in the hippocampal CA1 sector, thalamus, substantia nigra, and cerebellum, compared with young animals (1 month old). [3H]IP3 binding revealed significant elevations in the nucleus accumbens, hippocampal CA1 sector, dentate gyrus, and a significant reduction in cerebellum of middle-aged gerbils. [3H]Forskolin binding in middle-aged animals was significantly increased in the nucleus accumbens and hilus of dentate gyrus, but was diminished in the substantia nigra and cerebellum. On the other hand, in middle-aged animals, [3H]cyclic-AMP binding revealed a significant elevation only in the hippocampal CA3 sector, whereas [3H]rolipram binding showed a significant reduction in the thalamus and cerebellum. Thus, the age-related alteration in these binding sites showed different patterns among various brain regions in middle-aged gerbils indicating that the binding sites of PKC, IP3, and adenylate cyclase are more markedly affected by aging than those of PKA and cyclic-AMP PDE and that the hippocampus and cerebellum are more susceptible to these aging processes than other brain regions. The findings suggest that intracellular signal transduction is affected at an early stage of senescence and this may lead to neurological deficits.
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PMID:Age-dependent changes in second messenger and rolipram receptor systems in the gerbil brain. 787 23

Several lines of evidence suggest that cyclic GMP might be involved in long-term potentiation (LTP) in the hippocampus. Arachidonic acid, nitric oxide and carbon monoxide, three molecules that have been proposed to act as retrograde messengers in LTP, all activate soluble guanylyl cyclase. We report here that an inhibitor of guanylyl cyclase blocks the induction of LTP in the CA1 region of hippocampal slices. Conversely, cGMP analogues produce long-lasting enhancement of the excitatory postsynaptic potential if they are applied at the same time as weak tetanic stimulation of the presynaptic fibres. The enhancement is spatially restricted, is not blocked by valeric acid (APV), nifedipine, or picrotoxin, and partially occludes LTP. This synaptic enhancement may be mediated by the cGMP-dependent protein kinase (PKG). Inhibitors of PKG block the induction of LTP, and activators of PKG produce activity-dependent long-lasting enhancement. These results suggest that guanylyl cyclase and PKG contribute to LTP, possibly as activity-dependent presynaptic effectors of retrograde messengers.
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PMID:Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation. 790 17

We have investigated the effects of inhibitors of protein kinases and protein phosphatases on the NMDA receptor-independent potentiation of evoked and miniature (m) excitatory postsynaptic currents (EPSCs) induced by the entry of Ca2+ via voltage-gated Ca2+ channels in hippocampal CA1 pyramidal neurons. Voltage pulse-induced potentiation was markedly attenuated when evoked in the presence of the protein kinase blockers KN-62, K-252a, or H-7. Bath application of the protein phosphatase inhibitor calyculin A converted the usual transient potentiation of both evoked and spontaneous EPSCs induced by voltage pulses into a more sustained potentiation. Similarly, the introduction of the phosphatase inhibitors microcystin LR or okadaic acid into postsynaptic cells, via patch pipettes, also resulted in a sustained increase in the amplitude of mEPSCs. We propose that entry of Ca2+ into CA1 neurons activates calcium/calmodulin-dependent protein kinase II, which leads to an enhanced responsiveness of synaptic AMPA receptor channels. The enhancement is transient, however, owing to postsynaptic phosphatase activity.
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PMID:A role for protein kinases and phosphatases in the Ca(2+)-induced enhancement of hippocampal AMPA receptor-mediated synaptic responses. 791 94

Both CA1 and dentate gyrus regions of the hippocampal slice exhibit an irreversible loss of synaptic transmission after exposure to in vitro ischemic conditions (buffer without oxygen and glucose). However, after shorter durations of ischemia (8-10 min) the CA1 region shows an irreversible loss of synaptic responses, whereas the dentate gyrus region completely recovers synaptic responses upon reoxygenation. To determine biochemical mechanisms underlying this differential susceptibility, we have examined changes in Ca2+/calmodulin-dependent protein kinase II (CaM-KII) and cyclic AMP-dependent protein kinase activities in homogenates from CA1 and dentate gyrus regions of the hippocampal slice after increasing durations of in vitro ischemia. Time-dependent changes in CaM-KII activities were correlated with changes in electrophysiological responses. CA1 homogenates from slices exposed to 1 min of ischemia showed significant increases in CaM-KII activity, whereas there was no significant change in kinase activity in dentate homogenates after 1 min of ischemia. However, after longer durations of ischemia (5, 10, and 20 min) we found a time-dependent reduction in CaM-KII activity in both CA1 and dentate gyrus regions, whereas no change was detected in cyclic AMP-dependent protein kinase activity. Irreversible depression of CaM-KII activity was seen at shorter durations of ischemia (10 min) in the CA1 region than in dentate region (20 min), which correlated with irreversible effects on synaptic responses. Immunoblot analysis showed that the decrease in CaM-KII activity was not due to degradation of CaM-KII protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activity of Ca2+/calmodulin-dependent protein kinase II following ischemia: a comparison between CA1 and dentate gyrus in a hippocampal slice model. 796 41

1. The relationship of the activation of a voltage-sensitive chloride conductance [GCl(V)] to the chloride transmembrane equilibrium potential (ECl) and the consequent role of this conductance in determining the effect of the gamma-aminobutyric acid-A (GABAA) receptor-mediated transmembrane chloride (Cl-) flux were investigated with the use of whole-cell recordings in the CA1 and dentate gyrus regions of adult rat hippocampal slice preparations. 2. GCl(V) was inwardly rectifying, with significant conductance only at membrane potentials more negative than ECl. For all tested neuronal Cl- concentrations, the activation of GCl(V) could be described by a Boltzman equation with an average half-activation voltage 15 mV negative to ECl, a slope factor of 14 mV, and a maximum conductance of 5 microS. There was no time-dependent inactivation of GCl(V). 3. GCl(V) was modulated by intracellular divalent cations. When magnesium was omitted from the electrode solution, the inward rectification of GCl(V) was unchanged, but the maximum amplitude of GCl(V) increased by a factor of 1.7. GCl(V) was blocked by bath application of 100 microM zinc (Zn2+), but not when 1-6 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) or bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) were present in the electrode solution. 4. GCl(V) was increased by 10 microM norepinephrine, and by activation of protein kinase A (PKA) with 1 mM 8-bromoadenosine cyclic monophosphate (8-Br cAMP). GCl(V) was blocked by activation of protein kinase C (PKC) with 10 microM phorbol 12,13-dibutyrate (PdBu) or 1-oleoyl-2-acetyl-sn-glycerol (OAG). 5. GCl(V) was present in all tested CA1 pyramidal neurons but no dentate gyrus neurons. In standard extracellular solution, the amplitude of GCl(V) was initially negligible but increased with recording time, suggesting that under normal conditions GCl(V) is blocked by an endogenous divalent cation or downregulated by PKC. 6. In current-clamp recordings, the steady-state resting membrane potential (RMP) diminished with Cl- loading, from -73 mV (4 mM electrode Cl-) to -27 mV (131 mM electrode Cl-). When GCl(V) was blocked with PdBu, there was no change in the RMP with Cl- loading. When electroneutral Cl- transport was blocked, voltage-clamp experiments using electrode Cl- concentrations of 4-131 mM demonstrated that ECl changed in parallel with the holding potential, but not when GCl(V) was blocked by PdBu.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of an inwardly rectifying chloride conductance in postsynaptic inhibition. 796 11

Studies carried out with mammals and invertebrates suggest that Ca(2+)-sensitive adenylyl cyclases may be important for neuroplasticity. Long-term potentiation in the hippocampus requires increases in intracellular Ca2+ which are accompanied by elevated cyclic AMP (cAMP). Furthermore, activation of cAMP-dependent protein kinase is required for the late stage of long-term potentiation in the CA1 region of the hippocampus, which is also sensitive to inhibitors of transcription. Therefore, some forms of synaptic plasticity may require coordinate regulation of transcription by Ca2+ and cAMP. In this study, we demonstrate that the expression of type I adenylyl cyclase in HEK-293 cells allows Ca2+ to stimulate reporter gene activity mediated through the cAMP response element. Furthermore, simultaneous activation by Ca2+ and isoproterenol caused synergistic stimulation of transcription in HEK-293 cells and cultured neurons. We propose that Ca2+ and neurotransmitter stimulation of type I adenylyl cyclase may play a role in synaptic plasticity by generating optimal cAMP signals for regulation of transcription.
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PMID:Type I adenylyl cyclase functions as a coincidence detector for control of cyclic AMP response element-mediated transcription: synergistic regulation of transcription by Ca2+ and isoproterenol. 796 63

Recent studies of long-term potentiation (LTP) in the CA1 region of the hippocampus have demonstrated that nitric oxide (NO) may be involved in some forms of LTP and have suggested that postsynaptically generated NO is a candidate to act as a retrograde messenger. However, the molecular target(s) of NO in LTP remain to be elucidated. The present study examined whether either of two potential NO targets, a soluble guanylyl cyclase or an ADP-ribosyltransferase (ADPRT; EC 2.4.2.31) plays a role in LTP. The application of membrane-permeant analogs of cGMP did not produce any long-lasting alterations in synaptic strength. In addition, application of a cGMP-dependent protein kinase inhibitor did not prevent LTP. We found that the CA1 tissue from hippocampus possesses an ADPRT activity that is dramatically stimulated by NO and attenuated by two different inhibitors of mono-ADPRT activity, phylloquinone and nicotinamide. The extracellular application of these same inhibitors prevented LTP. Postsynaptic injection of nicotinamide failed to attenuate LTP, suggesting that the critical site of ADPRT activity resides at a nonpostsynaptic locus. These results suggest that ADP-ribosylation plays a role in LTP and are consistent with the idea that an ADPRT may be a target of NO action.
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PMID:An ADP-ribosyltransferase as a potential target for nitric oxide action in hippocampal long-term potentiation. 799 64

We have been investigating the hypothesis that the membrane-permeant molecules nitric oxide (NO) and carbon monoxide (CO) may act as retrograde messengers during long-term potentiation (LTP). Inhibitors of either NO synthase or heme oxygenase, the enzyme that produces CO, blocked induction of LTP in the CA1 region of hippocampal slices. Brief application of either NO or CO to slices produced a rapid and long-lasting increase in the size of synaptic potentials if, and only if, the application occurred at the same time as weak tetanic stimulation of the presynaptic fibers. The long-term enhancement by NO or CO was spatially restricted to synapses from active presynaptic fibers and appeared to involve mechanisms utilized by LTP, occluding the subsequent induction of LTP by strong tetanic stimulation. The enhancement by NO or CO was not blocked by the NMDA receptor blocker APV, suggesting that NO and CO act downstream from the NMDA receptor. In other systems, both NO and CO produce many of their effects by activation of soluble guanylyl cyclase and cGMP-dependent protein kinase. An inhibitor of soluble guanylyl cyclase blocked the induction of normal LTP. Conversely, the membrane-permeable analog 8-Br-cGMP produced a rapid onset and long-lasting synaptic enhancement if, and only if, it was applied at the same time as weak presynaptic stimulation. Similarly, two inhibitors of cGMP-dependent protein kinase blocked the induction of normal LTP, and a selective activator of cGMP-dependent protein kinase produced activity-dependent long-lasting synaptic enhancement. 8-Br-cGMP also produced an activity-dependent, long-lasting increase in the amplitude of evoked synaptic currents between pairs of hippocampal neurons in dissociated cell culture. In addition, 8-Br-cGMP, like NO, produced a long-lasting increase in the frequency of spontaneous miniature synaptic currents. These results are consistent with the hypothesis that NO and CO, either alone or in combination, serve as retrograde messengers that produce activity-dependent presynaptic enhancement, perhaps by stimulating soluble guanylyl cyclase and cGMP-dependent protein kinase, during LTP in hippocampus.
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PMID:Nitric oxide and carbon monoxide as possible retrograde messengers in hippocampal long-term potentiation. 807 65

Sequential alterations in the binding of [3H]cyclic AMP (cAMP) as an indicator of cAMP-dependent protein kinase (cAMP-DPK) binding activity following transient cerebral ischaemia were studied in the gerbil brain using receptor autoradiography. Transient ischaemia was induced for 10 min. [3H]cAMP binding in the stratum oriens and pyramidale of the hippocampal CA1 sector significantly decreased in the early post-ischaemic stage and showed severe reduction 7 days and 1 month after recirculation. By contrast, [3H]cAMP binding showed no significant alterations in the stratum radiatum of the hippocampal CA1 sector and the stratum pyramidale of the hippocampal CA3 sector up to 48 h after ischaemia. However, the binding in these areas significantly decreased 7 days and 1 month after ischaemia. The stratum lacunosum-moleculare of the hippocampal CA1 sector and dentate gyrus showed no significant changes in [3H]cAMP binding throughout the recirculation period. However, in the dorsolateral part of the striatum, where severe neuronal damage was seen morphologically, [3H]cAMP binding was significantly reduced only one month after ischaemia. These results indicate that marked alteration of intracellular signal transduction precedes neuronal damage in the hippocampal CA1 sector, but not in the striatum. Furthermore, our autoradiographic data suggest that post-ischaemic alteration in [3H]cAMP binding between the hippocampal CA1 sector and striatum may be produced by different mechanisms.
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PMID:Sequential changes of [3H]cyclic AMP binding in the gerbil brain following transient cerebral ischaemia. 810 69


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