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)

Bilateral occlusion of common carotid arteries in Mongolian gerbils was produced for the periods (up to 15 min) which were shown to be totally reversible. There was an initial increase of cyclic AMP and GABA levels and enhanced activities of adenylate cyclase and glutamate decarboxylase, as well as the reduction of norepinephrine level and decreased activities of monoamine oxidase, GABA-transaminase and Na+-K+-ATPase. Following these changes, decreased concentration of dopamine, serotinin and glutamate were found. The activities of total protein kinase and acetylcholinesterase were found to be reduced after longer periods of short-term ischemia. The data are consistent with the concept of increased non-controled release of putative neurotransmitters in ischemia.
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PMID:Alterations of putative neurotransmitters and enzymes during ischemia in gerbil cerebral cortex. 3 75

A monoclonal antibody against GM3 ganglioside (GM3Ab) was found to trigger differentiation of Neuro-2a cells in culture. The differentiation of Neuro-2a cells by GM3Ab was accompanied by increased levels of intracellular serotonin and amino acid neurotransmitters viz. aspartate, glutamate, glutamine, glycine and taurine. Further study indicated that the increase in the serotonin level was not due to a higher rate of serotonin synthesis but rather to a higher rate of active transport of serotonin from the medium. Studies on the cell surface gangliosides revealed that unlike the proliferating cells, the GM3Ab-mediated differentiated cells contained higher gangliosides in addition to GM3 and GM2 gangliosides. Analysis of total cellular proteins indicated the appearance of a 25 kDa protein, pI 5.4, in the GM3Ab-treated cells--a small amount of this protein was observed in dibutyryl cAMP (Bt2cAMP)-treated cells, however, the protein was totally absent in the 5-bromo-2'-deoxyuridine (BrdU)-treated cells. Investigation of the mode of action of GM3Ab indicated that the cellular differentiation was due to increased cAMP accumulation resulting from an increase in the adenylate cyclase activity. Further studies with different agents affecting protein kinase C (PKC) activity and direct assay of PKC ruled out the possibility that GM3Ab mediated its effect via PKC. This GM3Ab-induced differentiation could be inhibited by protein kinase A (PKA) inhibitor, H8, but could not be inhibited by sphingosine, an inhibitor of PKC. Pertussis toxin could mimic the effect of GM3Ab, suggesting that GM3Ab caused the elevation in the adenylate cyclase activity by reducing the Gi-protein inhibition of the adenylate cyclase. The data suggests that GM3Ab, after interaction with cell surface GM3, elevated intracellular cAMP level by withdrawing the inhibitory effect of some undefined factor(s) present in culture medium which normally keeps adenylate cyclase activity low through activation of Gi-protein.
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PMID:Differentiation of Neuro-2a neuroblastoma cells by an antibody to GM3 ganglioside. 132 94

Long-term desensitization of the AMPA-selective glutamate receptors in Purkinje cells was examined in rat cerebellar slices by means of the wedge recording method. It was not induced by application of AMPA alone, but occurred regularly when slices were conditioned by perfusion with 0.5 mM 8-bromo-cGMP (but not cAMP derivatives) or the protein phosphatase inhibitors, okadaic acid and calyculin A. Phorbol esters also showed a similar effect. The 8-bromo-cGMP desensitization was antagonized by KT5823, an inhibitor of protein kinase G, while the effect of calyculin A was inhibited by polymyxin B, H-7, or K252a. These results suggest that AMPA receptors are persistently desensitized due to concerted action of both an agonist and an enzymatic system involving protein kinases G and C and a protein phosphatase inhibitor.
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PMID:Protein kinases and phosphatase inhibitors mediating long-term desensitization of glutamate receptors in cerebellar Purkinje cells. 132 54

Long-term potentiation (LTP) is an example of a persistent change in synaptic function in the mammalian brain, thought to be essential for learning and memory. At the synapse between hippocampal CA3 and CA1 neurons LTP is induced by a Ca2+ influx through glutamate receptors of the NMDA (N-methyl-D-aspartate) type (see Collingridge et al 1992, this volume). How does a rise in [Ca2+]i lead to enhancement of synaptic function? We have tested the popular hypothesis that Ca2+ acts via a Ca(2+)-dependent protein kinase. We found that long-lasting synaptic enhancement was prevented by prior intracellular injection of potent and selective inhibitory peptide blockers of either protein kinase C (PKC) or Ca2+/calmodulin-dependent protein kinase II (CaMKII), such as PKC(19-31) or CaMKII(273-302), but not by control peptides. Evidently, activity of both PKC and CaMKII is somehow necessary for the postsynaptic induction of LTP. To determine if these kinases are also involved in the expression of LTP, we impaled cells with microelectrodes containing protein kinase inhibitors after LTP had already been induced. Strikingly, established LTP was not suppressed by a combination of PKC and CaMKII blocking peptides, or by intracellular postsynaptic H-7. However, established LTP remained sensitive to bath application of H-7. Thus, the persistent signal may be a persistent kinase, but if so, the kinase cannot be accessed within the postsynaptic cell. Evidence for a presynaptic locus of expression comes from our studies of quantal synaptic transmission under whole-cell voltage clamp. We find changes in synaptic variability expected to result from enhanced presynaptic transmitter release, but little or no increase in quantal size. Furthermore, miniature synaptic currents in hippocampal cultures are increased in frequency but not amplitude as a result of a glutamate-driven postsynaptic induction. The combination of postsynaptic induction and presynaptic expression necessitates a retrograde signal from the postsynaptic cell to the presynaptic terminal.
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PMID:Persistent signalling and changes in presynaptic function in long-term potentiation. 132 79

The transmitter dopamine reduces electrotonic coupling between retinal horizontal cells and increases their sensitivity to glutamate. Since in other systems single afferents establish mixed electrotonic and chemical excitatory synapses with their targets, dopamine might be expected there to depress one component of excitation while enhancing the other. This hypothesis was tested by applying dopamine locally in the vicinity of the lateral dendrite of the goldfish Mauthner cell (M cell) and monitoring the composite electrotonic and chemical excitatory postsynaptic potentials and currents evoked by ipsilateral eighth nerve stimulation. Dopamine produces persistent enhancements of both components of the postsynaptic response while it also increases input conductance. All these dopamine actions are prevented by superfusing the brain with saline containing the dopamine D1 receptor antagonist SCH-23390. Postsynaptic injections of the cAMP-dependent protein kinase inhibitor (Walsh inhibitor, or PKI5-24) block the dopamine-induced changes in synaptic transmission, implicating a cAMP-dependent mechanism. Furthermore, there is a dopaminergic innervation of the M cell, as demonstrated immunohistochemically with antibodies against dopamine and the rate-limiting enzyme in its synthetic pathway, tyrosine hydroxylase. Varicose immunoreactive fibers lie in the vicinity of the distal part of the lateral dendrite between the large myelinated club endings that establish the mixed synapses. As determined with electron microscopy, the dopaminergic fibers contain small vesicles, and they do not have synaptic contacts with either the afferents or the M cell, remaining instead in the synaptic bed. Taken together, these results suggest that dopamine released at a distance from these terminals increases the gain of this primary sensory input to the M cell, most likely through a phosphorylation mechanism.
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PMID:Dopamine enhances both electrotonic coupling and chemical excitatory postsynaptic potentials at mixed synapses. 133 56

Excitatory synaptic transmission in the central nervous system (CNS) is mediated by three major classes of glutamate receptors, namely the ionotropic NMDA (N-Methyl-D-Aspartate) and KA/AMPA (kainate/alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid) receptors and the metabotropic receptor type. Among the ionotropic receptors, NMDA receptors are thought to mediate their physiological response mainly through the influx of extracellular calcium, while KA/AMPA receptor channels are mainly thought to carry the influx of monovalent cations. Recently, we have challenged this view by showing that cloned KA/AMPA receptor subunits GluR1 and GluR3 form ion channels which are permeable to calcium. We now directly demonstrate large increases in intracellular calcium concentrations induced by calcium fluxes through KA/AMPA receptor channels in solutions with physiological calcium concentrations. Calcium fluxes were observed through glutamate receptor channels composed of the subunits GluR1 and GluR3, which are both abundantly present in various types of central neurones. The calcium influx was fluorometrically monitored in Xenopus oocytes injected with the calcium indicator dye fura-2. Bath application of the membrane permeable analogue of adenosine cyclic monophosphate (cAMP) potentiated the current and also the flux of calcium through open KA/AMPA receptor channels. Further pharmacological experiments suggested that this effect was mediated by the activation of protein kinase A. Our results provide a molecular interpretation for the function of calcium permeable KA/AMPA receptor channels in neurones and identify two of the subunits of the KA/AMPA receptor channel which are regulated by the cAMP dependent second messenger system.
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PMID:Calcium influx through subunits GluR1/GluR3 of kainate/AMPA receptor channels is regulated by cAMP dependent protein kinase. 137 54

Hypothermia was first applied therapeutically as a local anesthetic and later was used to achieve organ protection during procedures necessitating circulatory interruption. Profound whole-body hypothermia, typically carried out in conjunction with extracorporeal bypass, has long been employed during cardiac and neurosurgical operative procedures. More recently, studies in small-animal experimental models of cerebral ischemia have provided persuasive evidence that even small decreases in brain temperature confer striking protection against ischemic neuronal injury. By contrast, small elevations of brain temperature during ischemia accelerate and extend pathologic changes in the brain and promote early disruption of the blood-brain barrier. Hypothermia retards the rate of high-energy phosphate depletion during ischemia and promotes postischemic metabolic recovery. More importantly, mild intraischemic hypothermia markedly attenuates the release of glutamate into the brain's extracellular space and significantly diminishes the release of dopamine. Similarly, the inhibition of calcium-calmodulin-dependent protein kinase II triggered by normothermic ischemia is prevented by hypothermia, as is the ischemia-induced translocation and inhibition of the key regulatory enzyme protein kinase C. Hypothermia also appears to facilitate the resynthesis of ubiquitin following ischemia. Studies of potential clinical importance have shown that moderate hypothermia is capable of attenuating ischemic damage even if instituted early in the postischemic period. In the setting of focal cerebral ischemia, moderate brain hypothermia reduces the infarct size (particularly in the setting of reversible middle cerebral artery occlusion); conversely, hyperthermia markedly increases the infarct volume. These studies underscore the importance of monitoring and regulating the brain temperature during experimental studies of cerebral ischemia to insure a consistent pathologic outcome and to avoid the false attribution of "pharmacoprotection" to drugs that reduce the body temperature. The measurement of brain temperature is now practicable in neurosurgical patients requiring invasive monitoring, and human studies have shown that cortical and cerebroventricular temperatures may exceed systemic temperatures. Mild to moderate decreases in brain temperature are neuroprotective in cerebral ischemia, while mild elevations of brain temperature are markedly deleterious in the setting of ischemia or injury. It is anticipated that controlled clinical trials of therapeutic brain temperature modulation will be undertaken over the next several years.
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PMID:Therapeutic modulation of brain temperature: relevance to ischemic brain injury. 138 56

We have investigated the role of protracted phosphatase inhibition and the consecutive protracted protein phosphorylation on neuronal viability. We found that in primary cultures of cerebellar granule neurons, the protracted (24-h) inhibition of the serine/threonine protein phosphatases 1 and 2A (EC 3.1.3.16) by treatment of the cultures with okadaic acid (OKA; 5-20 nM) caused neurotoxicity that could be inhibited by the protein kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7) or by the previous down-regulation of the neuronal protein kinase C (PKC; ATP:protein phosphotransferase; EC 2.7.1.37). PKC was down-regulated by exposure of the cultures for 24 h to 100 nM phorbol 12-myristate 13-acetate (TPA). The effect of the drugs used in the viability studies on the pattern of protein phosphorylation was measured by quantitative autoradiography. In particular, the 50- and 80-kDa protein bands showed dramatic changes in the degree of phosphorylation: increase by OKA and brief TPA treatment; decrease by H7 or 24 h of TPA treatment; and inhibition of the OKA-induced increase by H7 or 24 h of TPA treatment. The results suggest that the protracted phosphorylation, in particular that mediated by PKC, may lead to neuronal death and are in line with our previous suggestion that prolonged PKC translocation is operative in glutamate neurotoxicity.
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PMID:Pathological phosphorylation causes neuronal death: effect of okadaic acid in primary culture of cerebellar granule cells. 140 5

Three effects of NT were observed on midbrain DA cells. The modulatory effect of NT, that is, the attenuation of DA-induced inhibition, has been most extensively examined. Studies indicate that this effect of NT was not simply due to a nonspecific excitation. NT selectively attenuated DA-induced inhibition without affecting either GABA-induced inhibition or glutamate-induced excitation of the same cells, and the attenuation of DA-induced inhibition could be observed at the doses at which the basal activity of DA cells was not changed by NT. The attenuation of DA-induced inhibition by NT is also unlikely to result from the formation of a DA-NT complex, since neuromedin N, which competes with NT for the same receptor but does not bind to DA, mimicked the effects, and neurotensin(1-11), which forms a complex with DA but is inactive in competing for NT receptors, did not. The similarities between the effects of NT and those of 8-bromo-cAMP and forskolin suggest that intracellular cAMP and protein kinase A may be involved. This suggestion was supported by the findings that IBMX (an inhibitor of phosphodiesterases) potentiated the effect of NT; and SQ22536 (an inhibitor of adenylate cyclase) and H8 (an inhibitor of protein kinase A) antagonized it. Phorbal-12,13-dibutyrate (an activator of protein kinase C) did not mimic the effect of neurotensin, and H7 (an inhibitor of protein kinase C) did not reduce the effect, suggesting that protein kinase C is unlikely to be involved in the modulatory effect of neurotensin. Experiments in vitro indicated that the excitatory effect of NT on DA cells occurred at higher concentrations (> 10 nM) than those needed for producing the modulatory effect. Its persistence during DA receptor blockade by sulpiride suggests that this effect was not entirely mediated by an attenuation of the inhibition induced by endogenously released DA. At even higher concentrations (> 100 nM), a sudden cessation of cell activity preceded by an increase in firing rate was observed. Whether this effect of NT was due to depolarization inactivation or a toxic effect of the peptide at high concentrations remains to be determined. In most other areas studied, the excitatory effect of NT was most commonly observed. In many areas, this excitatory effect was apparently a direct postsynaptic effect of NT. However, different mechanisms may be involved (see Table 1). For example, in some areas NT acted through a decrease in membrane conductance, while in others no change or an increase in the membrane conductance was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Actions of neurotensin: a review of the electrophysiological studies. 146 69

The purpose of this study is to examine whether monosodium L-glutamate (MSG) influences the function of pinealocytes in female rats. MSG was administered at a does of 4 mg/g body weight to rat pups on days 1 and 3 postnatally. As the rats matured, sexual receptivity as well as proceptivity were observed by testing the lordosis quotient (LQ), rejection quotient (RQ) and solicitation. Pineal function was estimated by measuring the serum level of melatonin and the activity of protein kinase A (PKA) in the pineal gland. Blood samples were withdrawn at light and dark phases for four consecutive days, respectively. The serum concentration of melatonin was determined by radioimmunoassay and the data of each phase were pooled together. The results showed that both the receptivity and proceptivity of MSG-treated female rats were significantly lower than that of the control ones. Melatonin levels during the dark phase were significantly higher than those during the light phase in both control and MSG-treated groups, but whenever in the light or dark phase, the levels of melatonin were the same in both groups. There was no significant difference in PKA activity in the pineal gland between the control and MSG-treated group. These results indicate that MSG used as a neurotoxin to induce hypogonadal status affected neither the PKA activity of pineal gland nor the serum level of melatonin in young female rats. Thus, the decrease in receptivity and proceptivity of MSG-treated female rats was not caused by the alteration of pineal function.
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PMID:[The effect of monosodium L-glutamate (MSG) treatment during neonatal period on the pineal function in young female rats]. 146 41


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