N-Methyl-d-aspartate Inhibits Apoptosis through Activation of Phosphatidylinositol 3-Kinase in Cerebellar Granule Neurons

Zhang, Frank X.; Rubin, Raphael; Rooney, Thomas

doi:10.1074/jbc.273.41.26596

Cited by 74 publications

(21 citation statements)

References 61 publications

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“…Because binding of the Src homology 2 domain of p85 to phosphotyrosine residues of target proteins increases PI-3K activity (39), NMDA receptors may directly activate PI-3K through protein-protein interactions. In addition, calcium/calmodulin has been reported to activate PI-3K (40), and it has been reported in cultured cerebellar granule neurons that NMDA-stimulated increases in intracellular calcium result in phosphorylation of insulin receptor sub- strate-1 and subsequent binding and activation of PI-3K (41).…”

Section: Discussionmentioning

confidence: 99%

N-Methyl d-Aspartate Receptor-mediated Bidirectional Control of Extracellular Signal-regulated Kinase Activity in Cortical Neuronal Cultures

Chandler¹,

Sutton²,

Dorairaj³

et al. 2001

Journal of Biological Chemistry

148

121

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, and PP2B did not prevent the inhibitory effect of NMDA. In the presence of tetrodotoxin, NMDA produced a bell-shaped dose-response curve with stimulation of phospho-ERK2 at 10, 25, and 50 M NMDA and reduced stimulation at 100 M NMDA. NMDA (50 M) stimulation of phospho-ERK2 was completely blocked by pertussis toxin and inhibitors of phosphatidylinositol 3-kinase and was partially blocked by a calcium/calmodulin-dependent kinase II inhibitor. These results suggests that NMDA receptors can bidirectionally control ERK signaling.Mitogen-activated protein kinases constitute a family of serine/threonine kinases, the best understood of which are the extracellular signal-regulated kinases (ERKs 1 ; Ref. 1). Ras proteins belong to a superfamily of small GTPases that cycle between inactive GDP-bound states and active GTP-bound states, and represent a point of convergence for the transduction and integration of many extracellular signals that activate mitogen-activated protein kinases (2). Ras-GTP initiates a sequential cascade of events involving recruitment to the membrane and activation of Raf-1, activation of the dual-specificity kinases termed mitogen-activated protein kinase/ERK kinases (MEKs), and finally activation of ERK. Activated ERKs phosphorylate cellular substrates and translocate to the nucleus, where they play an important role in regulating gene transcription (3, 4). In mitotic cells, ERKs constitute a primary effector pathway in controlling cellular proliferation, differentiation, cell cycle regulation, and survival. In brain, recent studies indicate that ERKs play an important role in synaptic plasticity and memory formation (5). Glutamate is the major excitatory neurotransmitter in the vertebrate brain, and the NMDA subtype of glutamate receptors are among the most widely distributed and abundant receptor-operated ion channels in the central nervous system. In addition to mediating the slow component of glutamate-dependent excitatory postsynaptic currents, NMDA receptors play a vital role in a variety of processes, including neuronal development, synaptic plasticity, learning and memory, and neuronal survival and death (6). NMDA receptor-mediated increases in intracellular calcium have been shown to stimulate ERK signaling, and evidence suggests that NMDA receptormediated ERK activation may play an important role in neurotransmission and synaptic plasticity (7,8). NMDA-dependent hippocampal long-term potentiation is associated with activation of ERK and is blocked by compounds that inhibit the ability of MEK to activate ERK (9, 10). ERK activation has also been shown to be required for hippocampal-dependent associative learning in rats (11), and mice lacking Ras-guanine nucleotide-releasing factor (Ras-GRF) display impaired amygdaladependent memory consolidation (12).

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Section: Discussionmentioning

confidence: 99%

N-Methyl d-Aspartate Receptor-mediated Bidirectional Control of Extracellular Signal-regulated Kinase Activity in Cortical Neuronal Cultures

Chandler¹,

Sutton²,

Dorairaj³

et al. 2001

Journal of Biological Chemistry

148

121

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“…PI 3-K activity was measured as described (5,16), with modifications. After treatment, CGCs were washed with buffer C (20 mM Tris⅐HCl, pH 7.4͞137 mM NaCl͞1 mM MgCl 2 ͞1 mM CaCl 2 ͞0.1 mM Na 3 VO 4 ) and lysed on ice with 1 ml of buffer C containing 1% Nonidet P-40 and 1 mM PMSF.…”

Section: Methodsmentioning

confidence: 99%

Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons

Chalecka-Franaszek

Chuang

1999

Proc. Natl. Acad. Sci. U.S.A.

504

358

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This report describes a modulatory action of lithium and glutamate on the activity of serine͞threonine kinase Akt-1. Lithium is most commonly used to treat bipolar disorder, but the mechanism of its therapeutic action remains unknown. We have recently demonstrated that lithium protects against glutamate-induced excitotoxicity in cultured brain neurons and in an animal model of cerebral ischemia. This study was undertaken to investigate the role of Akt-1, activated by the phosphatidylinositol 3-kinase (PI 3-K) signaling pathway, in mediating glutamate excitotoxicity and lithium protection in cerebellar granule cells. High levels of phosphorylation and activity of Akt-1 were detected in cerebellar neurons cultured in the presence of serum. Protracted treatment with selective PI 3-K inhibitors, wortmannin and LY294002, abolished Akt-1 activity and induced neuronal death that could be reduced by long-term lithium pretreatment. Exposure of cells to glutamate induced a rapid and reversible loss of Akt-1 phosphorylation and kinase activity. These effects were closely correlated with excitotoxicity and caspase 3 activation and were prevented by phosphatase inhibitors, okadaic acid and caliculin A. Long-term lithium pretreatment suppressed glutamate-induced loss of Akt-1 activity and accelerated its recovery toward the control levels. Lithium treatment alone induced rapid increase in PI 3-K activity, and Akt-1 phosphorylation with accompanying kinase activation, which was blocked by PI 3-K inhibitors. Lithium also increased the phosphorylation of glycogen synthase kinase-3 (GSK-3), a downstream physiological target of Akt. Thus, modulation of Akt-1 activity appears to play a key role in the mechanism of glutamate excitotoxicity and lithium neuroprotection.

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“…Rat cerebellar granule neurons were prepared from 7-day-old rat pups as reported previously (42,43). Briefly, cerebella were obtained from postnatal day 7 Harlan Sprague-Dawley rat pups, cross-chopped (400 ϫ 400 M), and then treated with 0.025% trypsin-EDTA (including 0.01% DNase I) for 15 min, 37°C.…”

Section: Methodsmentioning

confidence: 99%

Association of Heterotrimeric Gi with the Insulin-like Growth Factor-I Receptor

Hallak

Seiler

Green

et al. 2000

Journal of Biological Chemistry

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The insulin-like growth factor-I receptor (IGF-IR) is a key regulator of cell proliferation and survival. Activation of the IGF-IR induces tyrosine autophosphorylation and the binding of a series of adaptor molecules, thereby leading to the activation of MAPK. It has been demonstrated that pertussis toxin, which inactivates the G i class of GTP-binding proteins, inhibits IGF-I-mediated activation of MAPK, and a specific role for G ␤␥ subunits in IGF-I signaling was shown. In the present study, we have investigated the role of heterotrimeric G i in IGF-IR signaling in neuronal cells. Pertussis toxin inhibited IGF-I-induced activation of MAPK in rat cerebellar granule neurons and NG-108 neuronal cells. G ␣i and G ␤ subunits were associated with IGF-IR immunoprecipitates. Similarly, in IGF-IR-null mouse embryo fibroblasts transfected with the human IGF-IR, G i was complexed with the IGF-IR. G ␣s was not associated with the IGF-IR in any cell type. IGF-I induced the release of the G ␤ subunits from the IGF-IR but had no effect on the association of G ␣i . These results demonstrate an association of heterotrimeric G i with the IGF-IR and identify a discrete pool of G ␤␥ subunits available for downstream signaling following stimulation with IGF-I.Many receptors are coupled to heterotrimeric GTP-binding proteins (G-proteins). Prototypic G-protein coupled receptors (GPCRs) 1 contain a seven-membrane spanning region (1). Activated GPCRs bind to G-proteins and induce the release of G ␤␥ subunits from G ␣ subunits, which allows for the exchange of GDP for GTP on the G ␣ subunit. Activated G i subunits and G ␤␥ heterodimers interact with numerous signaling effectors, including adenylyl cyclase, ion channels, protein kinases, and phospholipases (2-4).In addition to their role in fully differentiated cells, GPCRs have been linked to mitogenesis and development (5-8). A specific role for G i in the induction of mitogenesis has been highlighted by the use of pertussis toxin, which inactivates G i by ADP-ribosylation of the G ␣ subunit. However, G ␣ subunits from several classes of G-proteins are not strongly mitogenic. Rather G ␤␥ heterodimer subunits activate a series of nonreceptor tyrosine kinases, which in turn activates p21 ras and extracellular signal-regulated kinases (or MAPK). Thus, G ␤␥ subunits serve to bridge intracellular signaling of classical GPCRs and mitogenic tyrosine kinase receptors (RTKs).G i also appears to be involved in the mitogenic actions of RTKs. Pertussis toxin variably inhibits the metabolic actions of insulin, both in vitro and in vivo (9 -16), and the insulin receptor may associate with G i (17)(18)(19). Importantly, mice with targeted knockout of G i have defects in insulin signaling (20). EGF-dependent signaling is also impaired by pertussis toxin in rat hepatocytes (21-23) and other cells (24 -27).The insulin-like growth factor-I receptor (IGF-IR), which has strong homology to the insulin receptor, exists as an ␣ 2 -␤ 2 -heterodimer and contains a cytoplasmic tyrosine kinase domain (28, 29). U...

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N-Methyl-d-aspartate Inhibits Apoptosis through Activation of Phosphatidylinositol 3-Kinase in Cerebellar Granule Neurons

Cited by 74 publications

References 61 publications

N-Methyl d-Aspartate Receptor-mediated Bidirectional Control of Extracellular Signal-regulated Kinase Activity in Cortical Neuronal Cultures

N-Methyl d-Aspartate Receptor-mediated Bidirectional Control of Extracellular Signal-regulated Kinase Activity in Cortical Neuronal Cultures

Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons

Association of Heterotrimeric Gi with the Insulin-like Growth Factor-I Receptor

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