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

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the role of the glycine recognition site of the N-methyl-D-aspartate receptor (the GlyNMDA site) in the facilitation of NMDA receptor agonist-evoked activity in rat dorsal horn neurons that is brought about by neurokinin1 (NK1) receptor agonist and the contribution of protein kinase C (PKC) activation to this phenomenon. Ionophoresis of the selective NMDA receptor agonist 1-aminocyclobutane-cis-1,3-dicarboxylic acid (ACBD) produced a sustained increase in the firing rate of single laminae III-V neurons recorded extracellularly using multibarrelled glass electrodes. The highly selective NK1 receptor agonist acetyl-[Arg6,Sar9,Met(O2)11]-SP6-11 (Sar9-SP) greatly facilitated this response, but under the present conditions had no effect when applied alone or with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor agonist) at the same current. In the presence of the GLyNMDA site antagonists 2-carboxy-4,6-dichloro-(1H)-indole-3-propanoic acid (MDL 29951), 7-chloro-3-(cyclopropylcarbonyl)-4-hydroxy-2(1H)-quinoline (L701,252), 5,7-dinitroquinaxoline-2,3-dione (MNQX) or 7-chlorothiokynurenic acid (7-CTK), or the PKC inhibitors, chelerythrine or GF109203X, the Sar9-SP-induced facilitation of ACBD-evoked activity was prevented, generally restoring activity to a level similar to that in the presence of ACBD alone, whilst an AMPA receptor antagonist, 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione (NBQX) did not inhibit the facilitation. At the same ionophoretic currents these compounds had no effect on ACBD-evoked activity in the absence of Sar9-SP but were inhibitory at significantly greater currents. To further substantiate the importance of the GlyNMDA site in the interaction, the effects of NMDA receptor antagonists selective for alternative recognition sites on the NMDA receptor were investigated. MK-801, a non-competitive NMDA receptor antagonist and arcaine, a competitive inhibitor at the polyamine site, were applied to the facilitated activity seen in the presence of Sar9-SP and ACBD, and to ACBD-evoked activity alone. Unlike the GlyNMDA site antagonists and PKC inhibitors, these compounds reduced both facilitated and ACBD-evoked activity at similar currents. Furthermore, like the NK1 receptor agonist, a selective GlyNMDA site agonist 1-aminocyclopropane carboxylic acid (ACPC) caused facilitation of ACBD-evoked activity which was also blocked by currents of L701,252 that did not alter activity evoked by ACBD alone. These data suggest that activation of the GlyNMDA site (perhaps as a consequence of glycine release or modification of its influence by intracellular signalling cascades) is an essential component of the means by which NK1 receptor activation results in facilitated responsiveness of dorsal horn neurons towards NMDA receptor agonists.
...
PMID:The glycine site of the NMDA receptor contributes to neurokinin1 receptor agonist facilitation of NMDA receptor agonist-evoked activity in rat dorsal horn neurons. 902 83

The effects of a nitric oxide synthase inhibitor, N omega-nitro-L-arginine (L-NARG), and a nitric oxide precursor, L-arginine (L-ARG), on the lipid peroxidation induced by quinolinic acid (QUIN, an NMDA receptor agonist), were both tested in synaptosomal fractions from whole rat brain. Baseline of lipid peroxidation was found at 2.43 +/- 0.24 fluorescence units/mg protein or 14.27 +/- 1.24 nmoles of TBARS/mg protein (100%). QUIN (100 microM)-induced lipid peroxidation in synaptosomes (256% and 166% vs. control, as measured by lipid fluorescent products and thiobarbituric acid-reactive substances, respectively) was inhibited by concentrations of 10, 40, 100, 200 and 400 microM of L-NARG (74%, 58%, 56%, 48% and 48% vs. quinolinate value, respectively). Coincubation of synaptosomes with QUIN plus L-ARG (100 microM), which alone resulted a potent pro-oxidant (277% vs. control), increased the lipoperoxidative effect induced by QUIN alone in 120% (290% vs. control). Synaptosomes simultaneously exposed to QUIN (100 microM) plus L-ARG (100 microM) plus L-NARG (200 microM) showed levels of lipid peroxidation similar to those of quinolinate alone. These findings suggest that nitric oxide may contribute to the oxidative damage induced in vitro by QUIN.
...
PMID:Effects of N omega-nitro-L-arginine and L-arginine on quinolinic acid-induced lipid peroxidation. 948 47

We have investigated the influence of the nitric oxide synthase (NOS) substrate, NG-hydroxy-L-arginine (H-ARG) on dopamine (DA) and glutamate (GLU) efflux in vivo using concentric microdialysis probes implanted in the anterior-medial striatum of chloral hydrate-anesthetized rats. Intrastriatal infusion of H-ARG (100 microM, 200 microM, or 1 mM for 120 min) increased DA efflux in a dose-dependent fashion. The facilitatory effect of H-ARG (1 mM) on DA efflux was abolished following pretreatment (80 min) with the constitutive NOS inhibitor 7-nitroindazole (7-NI, 10 microM) but unaffected by L-NG(1-iminoethyl) lysine (100 microM) infusion. As both H-ARG (1 mM) and the NO-generator (+/-)-S-nitroso-N-acetylpenicillamine (1 mM) were observed to increase GLU efflux concurrently with the effect on DA efflux, we evaluated the potential intermediary role of GLU in NO-facilitated DA efflux using ionotropic GLU receptor antagonists. Local infusion of dizocilpine maleate (10 microM) or (+/-)-2-amino-3-[3-(carboxymethoxy)-5-methyl-isoxazol-4-yl] propionic acid (100 microM), attenuated the H-ARG (1 mM)-induced elevation of extracellular DA levels. Conversely, similar treatment with the kainate receptor antagonist d-gamma-glutamyl-aminomethanesulfonic acid did not alter H-ARG-induced DA efflux. To evaluate the regulatory influence of striatal NO on NMDA receptor activation, NMDA (100 microM) was co-perfused with either H-ARG (2 mM) or 7-NI (10 microM). While co-perfusion with 7-NI potentiated NMDA-induced DA efflux, similar treatment with H-ARG (2 mM) abolished the effect. These results demonstrate that endogenous NO production, stimulated via H-ARG-dependent activation of type 1 NOS, enhances striatal DA efflux via an increase in glutamatergic tone on ionotropic GLU-receptors. At higher levels of NOS activation (following H-ARG (2 mM) or NMDA infusion), NO may block glutamatergic neurotransmission via inhibition of NMDA receptor function.
...
PMID:Endogenous nitric oxide facilitates striatal dopamine and glutamate efflux in vivo: role of ionotropic glutamate receptor-dependent mechanisms. 951 28

Nitric oxide (NO) is a potential contributor to neurotoxicity following overactivation of N-methyl-D-aspartate (NMDA) receptors. In this work we investigated the effect of Nomega-nitro-L-arginine (L-NARG 25, 50, or 100 microM), a selective inhibitor of nitric oxide synthase (NOS) -the synthetic enzyme of NO- on quinolinic acid (QUIN 100 microM)-induced neurotoxicity (measured as lactate dehydrogenase (LDH) leakage) in rat striatal slices. Oxidative stress was also measured both as lipid peroxidation and as the levels of reduced (GSH) and oxidized (GSSG) glutathione, in an effort to elucidate a possible participation of NO in the toxic mechanisms involved in NMDA receptor-mediated neuronal injury. The action of L-arginine (L-ARG 100 or 200 microM), a well-known NO precursor, was also tested on QUIN-induced neurotoxicity and oxidative stress. Results showed that QUIN produced significant changes in both cell damage (177%) and oxidative injury (203% in lipid peroxidation, 68% in GSH, and 123% in GSSG) as compared to control values. All these effects were antagonized by adding L-NARG to the incubation media, whereas L-ARG alone, or in combination with QUIN, significantly enhanced both lipid peroxidation and LDH leakage. Moreover, the protective effects of L-NARG on QUIN-induced lipid peroxidation were reversed by addition of an excess of L-ARG to the media. These findings indicate that NO is probably mediating the mechanism of neurotoxicity produced by QUIN, which may be of potential value to explain the molecular basis of neurodegenerative processes linked to QUIN-mediated NMDA receptor overactivation.
...
PMID:Nomega-nitro-L-arginine, a nitric oxide synthase inhibitor, antagonizes quinolinic acid-induced neurotoxicity and oxidative stress in rat striatal slices. 1040 23

Primary cortical neurones exposed to an oxidative insult in the form of hydrogen peroxide (H(2)O(2)) for 30 min showed a concentration-dependent increase in oxidative stress followed by a delayed NMDA receptor-dependent cell death measured 24 h later. Extracellular signal-regulated protein kinase (ERK1/2), c-jun N-terminal kinase (JNK) and the kinase Akt/PKB may regulate neuronal viability in response to oxidative insults. Using phospho-specific antibodies, a 15-min stimulation of neurones with H(2)O(2) (100 microm - 1 mm) produced a concentration-dependent phosphorylation of ERK1/2 and Akt/PKB that was partly dependent on extracellular Ca(2+) and phosphatidylinositol 3-kinase (PI3-K). Higher concentrations of H(2)O(2) (1 mm) also stimulated a phosphorylation of JNK which was totally dependent on extracellular Ca(2+) but not PI3-K. H(2)O(2)-induced phosphorylation of ERK1/2, Akt/PKB or JNK were unaffected by the NMDA channel blocker MK801. Blocking ERK1/2 activation with the upstream inhibitor U0126 (10 microm) enhanced H(2)O(2)-induced (100-300 microm range) neurotoxicity and inhibited H(2)O(2)-mediated phosphorylation of the cyclic AMP regulatory binding protein (CREB), suggesting that ERK1/2 signals to survival under these conditions. At higher concentrations (mm), H(2)O(2)-stimulated a phosphorylation of c-jun. It is likely, therefore, that subjecting neurones to moderate oxidative-stress recruits pro-survival signals to CREB but during severe oxidative stress pro-death signals through JNK and c-jun are dominant.
...
PMID:Hydrogen peroxide-mediated phosphorylation of ERK1/2, Akt/PKB and JNK in cortical neurones: dependence on Ca(2+) and PI3-kinase. 1179 40

Ca2+ influx through NMDA receptors can initiate molecular changes in neurones which may underlie synaptic plasticity, neuronal development, survival and excitotoxicity. Signalling through the MAP kinase (Erk1/2) cascade may be central to these processes. We previously demonstrated that Ca2+-permeable AMPA receptors activate Erkl/2 through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent mechanism. We now report that NMDA receptor activation of Erk1/2 was also blocked by inhibitors of PI 3-kinase (LY 294002, wortmannin). In addition, pre-treatment of neurones with pertussis toxin inhibited NMDA-induced Erk1/2 activation, indicating a role for heterotrimeric Gi/o proteins. PI 3-kinase directs activation of the serine-threonine kinase Akt (PKB). Treatment of striatal neurones with glutamate induced a rapid Ca2+-dependent and PI 3-kinase-dependent phosphorylation of Akt (Ser473), which was not blocked by the Mek inhibitors PD98059 or U0126. Targets for Erk1/2 and Akt pathways include transcription factors. Glutamate-induced phosphorylation of cAMP response element binding protein (CREB; Ser133) was partially blocked with either PD98059, U0126, LY294002 or wortmannin but was very strongly inhibited on co-application of LY294002 and PD98059. We propose that NMDA receptor stimulation can activate Erk1/2 and Akt signalling pathways in a PI 3-kinase dependent manner which may target CREB in the nucleus.
...
PMID:Phosphatidylinositol 3-kinase is a central mediator of NMDA receptor signalling to MAP kinase (Erk1/2), Akt/PKB and CREB in striatal neurones. 1190 14

Neuronal damage and death are consistent pathologic findings in the brains of patients with ADC, and multiple cell model systems have demonstrated neurotoxicity through the effects of HIV-1 infection in macrophages and microglia. Brain MRI studies (1H-MRS) indicate that reversible neuronal cell dysfunction occurs early during the course of HIV-1 infection, long before overt symptoms of ADC appear. Epidemiologic studies suggest that a high viral load in the CNS is a major risk factor for ADC and that HAART may significantly reduce, but not eliminate, the risk of developing ADC. Targeted adjunctive therapies administered early are likely necessary to maximize CNS protection against HIV, and rational approaches to such therapy are rapidly evolving through in vitro analysis of the mechanisms of HIV-associated neurotoxicity. Soluble factors released by infected cells may directly or indirectly damage neurons and induce apoptosis at the level of NMDA subtype of glutamate receptors, and NMDA receptor antagonists represent a major therapeutic option currently under intense clinical investigation. Likewise, drugs with antioxidant or free radical scavenging effects offer another rational approach to adjunctive therapy and are also under intense clinical scrutiny. Finally, agents that inhibit neuronal death-signaling pathways (e.g., p38 MAPK inhibitors) and that stimulate cell survival pathways (e.g., Akt/PKB) may represent the next investigational step in designing anti-ADC therapies.
...
PMID:Neuropathogenesis of central nervous system HIV-1 infection. 1224 93

Protein kinase B (PKB, or Akt), a downstream effector of phosphatidylinositol 3-kinase (PI-3-K), can play a critical role in regulating neuronal survival. Among known targets of PKB, glycogen synthase kinase-3 (GSK-3) is inhibited by PKB-mediated phosphorylation. Recent studies implicate GSK-3 as a physiologically relevant principal regulatory target of the PI-3-K/PKB survival pathway. Here we show that SB-216763 and SB-415286, selective small molecule inhibitors of GSK-3, protected cultured rat cerebellar granule neurons and hippocampal neurons against excitotoxicity mediated by NMDA and non-NMDA receptor agonists. Treatment with SB-216763 and SB-415286 was optimal when initiated 6-7 days before excitotoxin exposure. As GSK-3 can modulate transcriptional events, these results may provide insight into the identification of new neuroprotective targets.
...
PMID:Glycogen synthase kinase-3 inhibitors protect central neurons against excitotoxicity. 1296 Jul 65

Glutamate receptor activation of mitogen-activated protein (MAP) kinase signalling cascades has been implicated in diverse neuronal functions such as synaptic plasticity, development and excitotoxicity. We have previously shown that Ca2+-influx through NMDA receptors in cultured striatal neurones mediates the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt/protein kinase B (PKB) through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. Exposing neurones to the Src family tyrosine kinase inhibitor PP2, but not the inactive analogue PP3, inhibited NMDA receptor-induced phosphorylation of ERK1/2 and Akt/PKB in a concentration-dependent manner, and reduced cAMP response element-binding protein (CREB) phosphorylation. To establish a link between Src family tyrosine kinase-mediated phosphorylation and PI 3-kinase signalling, affinity precipitation experiments were performed with the SH2 domains of the PI 3-kinase regulatory subunit p85. This revealed a Src-dependent phosphorylation of a focal adhesion kinase (FAK)-p85 complex on glutamate stimulation. Demonstrating that PI3-kinase is not ubiquitously involved in NMDA receptor signal transduction, the PI 3-kinase inhibitors wortmannin and LY294002 did not prevent NMDA receptor Ca2+-dependent phosphorylation of c-Jun N-terminal kinase 1/2 (JNK1/2). Further, inhibiting Src family kinases increased NMDA receptor-dependent JNK1/2 phosphorylation, suggesting that Src family kinase-dependent cascades may physiologically limit signalling to JNK. These results demonstrate that Src family tyrosine kinases and PI3-kinase are pivotal regulators of NMDA receptor signalling to ERK/Akt and JNK in striatal neurones.
...
PMID:Inhibiting Src family tyrosine kinase activity blocks glutamate signalling to ERK1/2 and Akt/PKB but not JNK in cultured striatal neurones. 1500 68

Mechanical forces influence articular cartilage structure by regulating chondrocyte activity. Mechanical stimulation results in activation of an alpha5beta1 integrin dependent intracellular signal cascade involving focal adhesion kinase and protein kinase C, triggering the release of interleukin-4 from the cell. In normal HAC the response to physiological mechanical stimulation is characterised by increased levels of aggrecan mRNA and a decrease in levels of mRNA for matrix metalloproteinase 3 (MMP-3), the net result of which would be to maintain and optimise cartilage structure and function. This protective/anabolic response is not seen when chondrocytes from osteoarthritic cartilage are subjected to an identical mechanical stimulation regime. Following the observation that the neurotransmitter substance P is involved in chondrocyte mechanotransduction the present study was undertaken to establish potential roles for glutamate receptors in the control of chondrocyte mechanical responses. Using immunohistochemistry and RTPCR normal and OA chondrocytes are shown to express NR1 and NR2a subunits of the NMDA receptor. Addition of NMDA receptor agonists to chondrocytes in primary culture resulted in changes in membrane potential consistent with expression of functional receptors. NMDA receptor antagonists inhibited the hyperpolarisation response of normal chondrocytes to mechanical stimulation but had no effect on the depolarisation response of osteoarthritic chondrocytes to mechanical stimulation. These studies indicate that at least one subset of the NMDA receptor family of molecules is expressed in cartilage and may have important modulatory effects on mechanotransduction and cellular responses following mechanical stimulation. Indeed the results suggest that there is an alteration of NMDA receptor signalling in OA chondrocytes, which may be critical in the abnormal response of OA chondrocytes to mechanical stimulation. Thus NMDA receptors appear to be involved in the regulation of human articular chondrocyte responses to mechanical stimulation, and in OA, mechanotransduction pathways may be modified as a result of altered activation and function of these receptors.
...
PMID:NMDA receptor expression and roles in human articular chondrocyte mechanotransduction. 1529 60


1 2 3 Next >>

---