Akt mediates the anti‐apoptotic effect of NMDA but not that induced by potassium depolarization in cultured cerebellar granule cells

Lafon-Cazal, Mireille; Pérez, V.; Bockaert, Joël; Marin, Philippe

doi:10.1046/j.1460-9568.2002.02124.x

Cited by 61 publications

(67 citation statements)

References 48 publications

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“…In these neutrophils, C5a has been reported to inhibit apoptosis at least partially through the phosphatidylinositol 3-kinase/Akt pathway. Because phosphatidylinositol 3-kinase activation is known to inhibit apoptosis of granule neurons (61,62), this pathway could mediate the neuroprotective effect of MAP-C5a. C5aR is a G i protein-coupled receptor of the rhodopsin family (2, 3) known to activate the Ras/Raf/mitogen-activated protein kinase cascade through the phospholipase C/protein kinase C pathway in human neutrophils (63).…”

Section: Discussionmentioning

confidence: 99%

Characterization of C3a and C5a Receptors in Rat Cerebellar Granule Neurons during Maturation

Bénard

Gonzalez

Schouft

et al. 2004

Journal of Biological Chemistry

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There is now clear evidence that the Complement anaphylatoxin C3a and C5a receptors (C3aR and C5aR) are expressed in glial cells, notably in astrocytes and microglia. In contrast, very few data are available concerning the possible expression of these receptors in neurons. Here, we show that transient expression of C3aR and C5aR occurs in cerebellar granule neurons in vivo with a maximal density in 12-day-old rat, suggesting a role of these receptors during development of the cerebellum. Expression of C3aR and C5aR mRNAs and proteins was also observed in vitro in cultured cerebellar granule cells. Quantification of the mRNAs by real-time reverse transcription-PCR showed a peak of expression at day 2 in vitro (DIV 2); the C3aR and C5aR proteins were detected by Western blot analysis at DIV 4 and by flow cytometry and immunocytochemistry in differentiating neurons with a maximum density at DIV 4 -9. Apoptosis of granule cells plays a crucial role for the harmonious development of the cerebellar cortex. We found that, in cultured granule neurons in which apoptosis was induced by serum deprivation and low potassium concentration, a C5aR agonist promoted cell survival and inhibited caspase-3 activation and DNA fragmentation. The neuroprotective effect of the C5aR agonist was associated with a marked inhibition of caspase-9 activity and partial restoration of mitochondrial integrity. Our results provide the first evidence that C3aR and C5aR are both expressed in cerebellar granule cells during development and that C5a, but not C3a, is a potent inhibitor of apoptotic cell death in cultured granule neurons.

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Section: Discussionmentioning

confidence: 99%

Characterization of C3a and C5a Receptors in Rat Cerebellar Granule Neurons during Maturation

Bénard

Gonzalez

Schouft

et al. 2004

Journal of Biological Chemistry

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“…Ca 2 þ /calmodulin-dependent kinase kinase (CaM-KK) was reported to phosphorylate Akt on threonine-308 independently of PI3K and trigger Akt-dependent survival responses (Yano et al, 1998). The model of CaM-KK-dependent activation of Akt is attractive, also in view of the activation of Akt by N-methyl-D-aspartate (NMDA) (Bhave et al, 1999;Lafon-Cazal et al, 2002;Sutton and Chandler, 2002), but little additional evidence applicable to other AGC family kinases has been found to support this model (Imai et al, 2003). PKA itself is a substrate for PDK1-dependent phosphorylation, but it also activates Akt in a PI3K-independent manner by a mechanism that does not result in Akt phosphorylation on serine-473 (Sable et al, 1997;Filippa et al, 1999).…”

Section: Pdk1-independent Mechanisms Of Akt Activationmentioning

confidence: 99%

PI3K/Akt and apoptosis: size matters

et al. 2003

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Recent research has examined Akt and Akt-related serine-threonine kinases in signaling cascades that regulate cell survival and are important in the pathogenesis of degenerative diseases and in cancer. We seek to recapitulate the research that has helped to define the current understanding of the role of the Akt pathway under normal and pathologic conditions, also in view of genetic models of Akt function. In particular, we will evaluate the mechanisms of Akt regulation and the role of Akt substrates in Akt-dependent biologic responses in the decisions of cell death and cell survival. Here, we hope to establish the mechanisms of apoptosis suppression by Akt kinase as a framework for a more general understanding of growth factor-dependent regulation of cell survival.

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“…The phosphatidylinositol 3-kinase-Akt pathway mediates neuroprotection evoked by ongoing synaptic activity The phosphatidylinositol 3-kinase (PI3K)-Akt pathway (Brazil et al, 2004) is activated by NMDA receptor activity and has neuroprotective capabilities (Brunet et al, 2001;Lafon-Cazal et al, 2002). Moreover, bicuculline treatment activates Akt in an NMDA receptor-dependent manner (Fig.…”

Section: Activation Of Cre-mediated Gene Expression Is Not Needed Formentioning

confidence: 99%

Nuclear Ca²+ and the cAMP Response Element-Binding Protein Family Mediate a Late Phase of Activity-Dependent Neuroprotection

Papadia¹,

Stevenson²,

Hardingham³

et al. 2005

J. Neurosci.

251

299

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The mechanism by which physiological synaptic NMDA receptor activity promotes neuronal survival is not well understood. Here, we show that that an episode of synaptic activity can promote neuroprotection for a long time after that activity has ceased. This long-lasting or "late phase" of neuroprotection is dependent on nuclear calcium signaling and cAMP response element (CRE)-mediated gene expression. In contrast, neuroprotection evoked acutely by ongoing synaptic activity relies solely on the activation of the phosphatidylinositol 3-kinase/Akt pathway. This "acute phase" does not require nuclear calcium signaling and is independent of activation of the CRE-binding protein (CREB) family of transcription factors. Thus, activity-dependent neuroprotection comprises two mechanistically distinct phases that differ in their spatial requirements for calcium and in their reliance on the CREB family.

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Akt mediates the anti‐apoptotic effect of NMDA but not that induced by potassium depolarization in cultured cerebellar granule cells

Cited by 61 publications

References 48 publications

Characterization of C3a and C5a Receptors in Rat Cerebellar Granule Neurons during Maturation

Characterization of C3a and C5a Receptors in Rat Cerebellar Granule Neurons during Maturation

PI3K/Akt and apoptosis: size matters

Nuclear Ca²+ and the cAMP Response Element-Binding Protein Family Mediate a Late Phase of Activity-Dependent Neuroprotection

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Akt mediates the anti‐apoptotic effect of NMDA but not that induced by potassium depolarization in cultured cerebellar granule cells

Cited by 61 publications

References 48 publications

Characterization of C3a and C5a Receptors in Rat Cerebellar Granule Neurons during Maturation

Characterization of C3a and C5a Receptors in Rat Cerebellar Granule Neurons during Maturation

PI3K/Akt and apoptosis: size matters

Nuclear Ca2+ and the cAMP Response Element-Binding Protein Family Mediate a Late Phase of Activity-Dependent Neuroprotection

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Nuclear Ca²+ and the cAMP Response Element-Binding Protein Family Mediate a Late Phase of Activity-Dependent Neuroprotection