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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of GABA and its receptors early in rodent nervous system development has lead to speculation on the role of this transmitter system in neuroblast proliferation, migration and differentiation. We studied the effect of GABA and GABA agonists on immature cerebellar granule cell proliferation and survival. Cerebellar granule cell suspensions were obtained from 6-8-day-old rats and grown in culture for up to 7 days in serum-containing or serum-free medium. The addition of GABA (0.1-100 microM) or muscimol (0.01-10 microM) 2 h after inoculation and harvested 22 h later, lead to an increase in 3H-thymidine incorporation over control samples with the correspondent increase in granule cells number assayed 48 h later. The effect on cell proliferation exerted by GABAA agonists was blocked by MgCl2 and nifedipine, as well as by the chloride channel blocker, picrotoxin (50 microM), and the GABAA receptor specific blocker, bicuculline (50 microM). The increase on cell proliferation induced by GABA also was blocked by PD98059 (75 microM), a specific inhibitor of the mitogen-activated protein kinase kinase (MAPKK). GABAA receptor-mediated proliferation was consistently seen in cells inoculated in serum-containing medium supplemented with 25 mM KCl but not seen in serum-free medium, with 5 mM or 25 mM KCl. The presence of serum did not enhance the survival of cerebellar granule cells grown for 7 days in either 5 mM or 25 mM KCl. Additionally, neither GABA nor muscimol applied from day 2 to day 7 in vitro affected cell survival in any culture condition. We conclude that GABA and GABAA receptor agonists influence granule cell proliferation but not survival and that this effect is mediated by a calcium influx via voltage-dependent calcium channel activation, with a subsequent activation of the MAPK cascade.
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PMID:GABA induces proliferation of immature cerebellar granule cells grown in vitro. 1036 96

Brain-derived neurotrophic factor (BDNF) can regulate the maturation of developing cerebellar granule neurons. Within 1-2 days of culture, BDNF induces the expression of granule neuron terminal differentiation markers, particularly GABA(A) receptor alpha6 subunit (GABA(A)alpha6) mRNA. Other trophic factors including insulin-like growth factor, the neurotrophin NT-3, pituitary adenylate cyclase-activating polypeptide (PACAP), and fetal bovine serum failed to induce this early expression. The expression of other GABA(A) receptor subunits, including alpha1 and gamma2, was also enhanced by exposure of developing granule neurons to BDNF. This BDNF-dependent expression of GABA(A) receptor subunit mRNAs could be effectively blocked by treatment with the mitogen-activated protein kinase kinase (MEK) inhibitors, PD98059 or U0126. In the absence of BDNF, GABA(A)alpha6 expression occurs but not until 3-4 days of culture. This BDNF-independent expression of GABA(A)alpha6 was also inhibited by PD98059. Further studies showed that the BDNF-dependent expression GABA(A)alpha6 could also be reduced by LY294002, an inhibitor of the phosphatidylinositol 3-kinase, or depolarizing concentrations of KCl. These results thus suggest that both BDNF-dependent and -independent expressions of GABA(A) receptor subunits require the activation of MEK and the mitogen-activated protein kinase (MAPK) pathway. However, it is also likely that other signaling pathways modulate this maturation process.
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PMID:MEK inhibitors block BDNF-dependent and -independent expression of GABA(A) receptor subunit mRNAs in cultured mouse cerebellar granule neurons. 1064 67

A 30% decrease in osmolarity stimulated 3H-taurine, 3H-GABA and glutamate (followed as 3H-D-aspartate) efflux from rat hippocampal slices. 3H-taurine efflux was activated rapidly but inactivated slowly. It was decreased markedly by 100 microM 5-nitro-(3-phenylpropylamino)benzoic acid (NPPB) and 600 microM niflumic acid and inhibited strongly by tyrphostins AG18, AG879 and AG112 (25-100 microM), suggesting a tyrosine kinase-mediated mechanism. Hyposmolarity activated the mitogen-activated protein kinases (MAPK) extracellular-signal-related kinase-1/2 (ERK1/ERK2) and p38, but blockade of this reaction did not affect 3H-taurine efflux. Hyposmosis also activated phosphatidylinositide 3-kinase (PI3K) and its prevention by wortmannin (100 nM) essentially abolished 3H-taurine efflux. 3H-taurine efflux was insensitive to the protein kinase C (PKC) blocker chelerythrine (2.5 microM) or to cytochalasin E (3 microM). The release of 3H-GABA and 3H-D-aspartate occurred by a different mechanism, characterized by rapid activation and inactivation, insensitivity to NPPB, niflumic acid, tyrphostins or wortmannin. 3H-GABA and 3H-D-aspartate efflux was not due to external [NaCl] decrease, cytosolic Ca2+ increase or depolarization, or to reverse operation of the carrier. This novel mechanism of amino acid release may be mediated by Ca2+-independent exocytosis and modulated by PKC and actin cytoskeleton disruption, as suggested by its inhibition by chelerythrine and potentiation by 100 nM phorbol-12-myristate-13 acetate (PMA) and cytochalasin E. GABA and glutamate osmosensitive efflux may explain the hyposmolarity-elicited increase in amplitude of inhibitory and excitatory postsynaptic potentials in hippocampal slices as well as the hyperexcitability associated with hyponatraemia.
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PMID:Evidence for two mechanisms of amino acid osmolyte release from hippocampal slices. 1151 36

The circadian clock of the suprachiasmatic nuclei (SCN) of perinatal rodents is entrained by maternally derived cues. The SCN of neonatal Syrian hamsters express high-affinity D1 dopamine receptors, and the circadian activity-rest cycle of pups can be entrained by maternal injection of dopaminergic agonists. The present study sought to characterize the intracellular pathways mediating dopaminergic signalling in neonatal rodent SCN. Both dopamine and the D1 agonist SKF81297 caused a dose-dependent increase in phosphorylation of the transcriptional regulator Ca2+/cyclic AMP response element (CRE) binding protein (CREB) in suprachiasmatic GABA-immunoreactive (-IR) neurons held in primary culture. The D1 antagonist SCH23390 blocked this effect. Dopaminergic induction of pCREB-IR in GABA-IR neurons was also blocked by a protein kinase A (PKA) inhibitor, 5-24, and by the MAPK inhibitor, PD98059, whereas KN-62, an inhibitor of Ca2+/calmodulin-dependent (CAM) kinase II/IV was ineffective. Treatment with NMDA increased the level of intracellular Ca2+ in the cultured primary SCN neurons in Mg2+-free medium, but SKF81297 did not. Blockade of CaM kinase II/IV with KN-62 inhibited glutamatergic induction of pCREB-IR in GABA-IR neurons, whereas 5-24 was ineffective, confirming the independent action of Ca2+- and cAMP-mediated inputs on pCREB. SKF81297 caused an increase in pERK-IR in SCN cells, and this was blocked by 5-24, indicative of activation of MAPK via D1/cAMP. These results demonstrate that dopaminergic signalling in the neonatal SCN is mediated via the D1-dependent activation of PKA and MAPK, and that this is independent of the glutamatergic regulation via Ca2+ and CaM kinase II/IV responsible for entrainment to the light/dark cycle.
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PMID:Dopaminergic signalling in the rodent neonatal suprachiasmatic nucleus identifies a role for protein kinase A and mitogen-activated protein kinase in circadian entrainment. 1184 90

Ethanol (1.5-3.5 g/kg body weight) was administered intraperitoneally to mice and the phosphorylation of MAP (mitogen-activated protein) kinase in the cerebral cortex was determined using phospho-specific MAP kinase antibodies. Ethanol inhibited the phosphorylation of MAP kinase in a dose- and time-dependent manner. Developmental studies demonstrated that the levels of phospho-MAP kinase increased from fetal cortex (prenatal) to 16-day-old mice (postnatal) and remained constant up to 4 months of age. However, ethanol (3.5 g/kg) decreased the phospho-MAP kinase staining in all of the age groups studied. Subcellular fractionation studies demonstrated that ethanol inhibited the phosphorylation of MAP kinase in both the cytosol as well as nucleus, but did not alter the levels of MAP kinase. Likewise, MK-801 (0.4 mg/kg) or flurazepam (75 mg/kg) also decreased the phospho-MAP kinase content. These data indicate that ethanol may inhibit the phosphorylation of MAP kinase in vivo by either inhibiting NMDA receptors or activating GABA receptors.
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PMID:Ethanol-mediated inhibition of mitogen-activated protein kinase phosphorylation in mouse brain. 1193 92

During early neuronal development, GABA functions as an excitatory neurotransmitter, triggering membrane depolarization, action potentials, and the opening of plasma membrane Ca(2+) channels. These excitatory actions of GABA lead to a number of changes in neuronal structure and function. Although the effects of GABA on membrane biophysics during early development have been well documented, little work has been done to examine the possible mechanisms underlying GABA-regulated plastic changes in the developing brain. This study focuses on GABA-regulated kinase activity and transcriptional control. We utilized a combination of Western blotting and immunocytochemical techniques to examine two potential downstream pathways regulated by GABA excitation: the p42/44 mitogen-activated protein kinase (MAPK) cascade and the transcription factor cyclic AMP response element binding protein (CREB). During early development of cultured hypothalamic neurons (5 days in vitro), stimulation with GABA triggered activation of the MAPK cascade and phosphorylation of CREB at Ser 133. These effects were mediated by the GABA(A) receptor, since administration of the GABA(A) receptor-specific agonist muscimol (50 microM) triggered pathway activation, and pretreatment with the GABA(A)-receptor specific antagonist bicuculline (20 microM) blocked pathway activation. Immunocytochemistry revealed a spatial and temporal correlation between activation of the MAPK cascade and CREB phosphorylation. Pretreatment with the MAPK/ERK kinase (MEK) inhibitor U0126 (10 microM) attenuated CREB phosphorylation, indicating that the MAPK pathway regulates that activation state of CREB. In contrast to the excitatory effects observed during early development, in more mature neurons, GABA functions as an inhibitory transmitter. Consistent with this observation, GABA(A) receptor activation did not stimulate MAPK cascade activation or CREB phosphorylation in mature cultures (18 days in vitro). To determine whether GABA(A) receptor activation during early development stimulates gene expression, we examined the inducible expression of the neurotrophin brain-derived neurotrophic factor (BDNF). Both GABA and muscimol stimulated BDNF expression, and pretreatment with U0126 attenuated GABA-induced BDNF expression. Whole cell electrophysiological recording was used to assess the effects of BDNF on GABA release. BDNF (100 ng/ml) dramatically increased the frequency of excitatory GABAergic spontaneous postsynaptic currents. Together, these data suggest a positive excitatory feedback loop between GABA and BDNF expression during early development, where GABA facilitates BDNF expression, and BDNF facilitates the synaptic release of GABA. Signaling via the MAPK cascade and the transcription factor CREB appear to play a substantial role in this process.
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PMID:Excitatory actions of GABA increase BDNF expression via a MAPK-CREB-dependent mechanism--a positive feedback circuit in developing neurons. 1216 49

The chicken retina was exposed to 20% hyposmotic or ischaemia-like (54 mM KCl and 1 mM ouabain) conditions and changes in cell volume, amino acid release and activation of protein tyrosine kinases measured. To investigate possible connection between these cellular events, the effect of tyrosine kinase blockers on (3)H-taurine, (3)H-GABA and (3)H- D-aspartate (as a tracer for glutamate) efflux was examined. Both hyposmotic and ischaemic conditions increased phosphorylation of the tyrosine kinase p125 focal adhesion kinase (p125(FAK)) and the mitogen-activated protein kinase-p38 (MAPK-p38), but not of the extracellular-signal-related kinases-1/2 (ERK1/ERK2), and markedly activated the tyrosine kinase target enzyme phosphatidylinositide 3-kinase (PI3K). Hyposmolarity and ischaemia both led to rapid retinal swelling followed by active volume recovery of 84% (hyposmolarity) and 40% (ischaemia), together with rapid release of taurine, GABA and D-aspartate. Taurine and GABA efflux under both conditions was reduced markedly by tyrosine kinase and PI3K blockers (50 microM tyrphostin A23, 50 microM genistein, 100 nM wortmannin, 25 microM LY294002) and was decreased by 85% when ischaemia-induced swelling was prevented. About 65% of D-aspartate efflux occurred irrespective of swelling in ischaemia and was either less sensitive (hyposmotic) or largely resistant (ischaemia) to the blockers. These results suggest that in ischaemia, GABA and taurine react primarily to swelling with a typical osmolyte response, while glutamate differs in its release mechanisms under both hyposmotic and ischaemic conditions. These findings suggest new strategies for evaluating the contribution of swelling to excitotoxicity in ischaemia.
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PMID:Tyrosine kinases and amino acid efflux under hyposmotic and ischaemic conditions in the chicken retina. 1239 92

The mechanisms by which cells adapt and respond to changes in oxygen tension remain largely unknown. Our laboratory has used the PC12 cell line to study both biophysical and molecular responses to hypoxia. This chapter summarizes our findings. We found that membrane depolarization that occurred when PC12 cells were exposed to reduced O(2) was mediated by a specific potassium channel, the Kv1.2 channel. The membrane depolarization leads to increased Ca(2+) conductance through a voltage-sensitive channel, which in turn mediates the release of the neurotransmitters dopamine, adenosine, glutamate, and GABA. In addition, increased intracellular Ca(2+) and other signaling systems regulate hypoxia-induced gene expression, which contributes to the adaptive response to reduced O(2+). We identified several critical signaling pathways that regulate a complex gene expression profile in PC12 cells during hypoxia. These include the cAMP-protein kinase A, Ca(2+)-calmodulin, p42/44 mitogen-activated protein kinase (MAPK), stress-activated protein kinase (SAPK; p38 kinase), and the phosphatidylinositol 3-kinase-AKT as regulators of gene expression. Several of these pathways regulate hypoxia-specific transcription factors that are members of the hypoxia-inducible factor (HIF) family. Recently, we have successfully used subtractive cDNA libraries and microarray analysis to identify the genomic profile that mediates the cellular response to hypoxia.
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PMID:Genomic and physiological analysis of oxygen sensitivity and hypoxia tolerance in PC12 cells. 1243 56

GABA and its type A receptor (GABA(A)R) are present in the immature CNS and may function as growth-regulatory signals during the development of embryonic neural precursor cells. In the present study, on the basis of their isopycnic properties in a buoyant density gradient, we developed an isolation procedure that allowed us to purify proliferative neural precursor cells from early postnatal rat striatum, which expressed the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). These postnatal striatal PSA-NCAM+ cells were shown to proliferate in the presence of epidermal growth factor (EGF) and formed spheres that preferentially generated neurons in vitro. We demonstrated that PSA-NCAM+ neuronal precursors from postnatal striatum expressed GABA(A)R subunits in vitro and in situ. GABA elicited chloride currents in PSA-NCAM+ cells by activation of functional GABA(A)R that displayed a typical pharmacological profile. GABA(A)R activation in PSA-NCAM+ cells triggered a complex intracellular signaling combining a tonic inhibition of the mitogen-activated protein kinase cascade and an increase of intracellular calcium concentration by opening of voltage-gated calcium channels. We observed that the activation of GABA(A)R in PSA-NCAM+ neuronal precursors from postnatal striatum inhibited cell cycle progression both in neurospheres and in organotypic slices. Furthermore, postnatal PSA-NCAM+ striatal cells synthesized and released GABA, thus creating an autocrine/paracrine mechanism that controls their proliferation. We showed that EGF modulated this autocrine/paracrine loop by decreasing GABA production in PSA-NCAM+ cells. This demonstration of GABA synthesis and GABA(A)R function in striatal PSA-NCAM+ cells may shed new light on the understanding of key extrinsic cues that regulate the developmental potential of postnatal neuronal precursors in the CNS.
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PMID:Autocrine/paracrine activation of the GABA(A) receptor inhibits the proliferation of neurogenic polysialylated neural cell adhesion molecule-positive (PSA-NCAM+) precursor cells from postnatal striatum. 1271 35

gamma-Hydroxybutyrate (GHB) naturally occurs in the brain, but its exogenous administration induces profound effects on the central nervous system in animals and humans. The intracellular signaling mechanisms underlying its actions remain unclear. In the present study, the effects of GHB on the activation (phosphorylation) of mitogen-activated protein kinases (MAP kinases), extracellular signal-regulated kinase 1 and 2 (ERK1/2), were investigated. Acute administration of GHB (500 mg/kg, intraperitoneal) induced a fast and long lasting inhibition of MAP kinase phosphorylation in both frontal cortex and hippocampus. The reduced MAP kinase phosphorylation was observed in the CA1 and CA3 areas but not in the dentate gyrus. Pretreatment with the specific gamma-aminobutyric acid, type B (GABAB), receptor antagonist CGP56999A (20 mg/kg, intraperitoneal) prevented the action of GHB, and the effect of GHB was mimicked by baclofen, a selective GABAB receptor agonist, whereas the high affinity GHB receptor antagonist NCS-382 (200 mg/kg, intraperitoneal) had no effect on GHB-inhibited MAP kinase phosphorylation. Moreover, the GHB dehydrogenase inhibitor valproate (500 mg/kg, intraperitoneal), which inhibits the conversion of GHB into GABA, failed to block the effect of GHB on MAP kinase phosphorylation. Altogether, these data suggest that GHB, administered in vivo, reduces MAP kinase phosphorylation via a direct activation of GABAB receptors by GHB. In contrast, GHB (10 mm for 15 min) was found ineffective on MAP kinase phosphorylation in brain slices, indicating important differences in the conditions required for the second messenger activating action of GHB.
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PMID:Gamma-hydroxybutyrate reduces mitogen-activated protein kinase phosphorylation via GABA B receptor activation in mouse frontal cortex and hippocampus. 1292 92


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