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Depolarization and neurotrophins converge on the phosphatidylinositol 3-kinase-Akt pathway to synergistically regulate neuronal survival.

Vaillant AR, Mazzoni I, Tudan C, Boudreau M, Kaplan DR, Miller FD - J. Cell Biol. (1999)

Bottom Line: This convergent PI3-kinase-Akt pathway was essential for synergistic survival.In contrast, inhibition of calcium/calmodulin-dependent protein kinase II revealed that, while this molecule was essential for depolarization-induced survival, it had no role in KCl- induced Akt phosphorylation, nor was it important for synergistic survival by NGF and KCl.This convergent regulation of Akt may provide a general mechanism for coordinating the effects of growth factors and neural activity on neuronal survival throughout the nervous system.

View Article: PubMed Central - PubMed

Affiliation: Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4.

ABSTRACT
In this report, we have examined the mechanisms whereby neurotrophins and neural activity coordinately regulate neuronal survival, focussing on sympathetic neurons, which require target-derived NGF and neural activity for survival during development. When sympathetic neurons were maintained in suboptimal concentrations of NGF, coincident depolarization with concentrations of KCl that on their own had no survival effect, synergistically enhanced survival. Biochemical analysis revealed that depolarization was sufficient to activate a Ras-phosphatidylinositol 3-kinase-Akt pathway (Ras-PI3-kinase-Akt), and function-blocking experiments using recombinant adenovirus indicated that this pathway was essential for approximately 50% of depolarization-mediated neuronal survival. At concentrations of NGF and KCl that promoted synergistic survival, these two stimuli converged to promote increased PI3-kinase-dependent Akt phosphorylation. This convergent PI3-kinase-Akt pathway was essential for synergistic survival. In contrast, inhibition of calcium/calmodulin-dependent protein kinase II revealed that, while this molecule was essential for depolarization-induced survival, it had no role in KCl- induced Akt phosphorylation, nor was it important for synergistic survival by NGF and KCl. Thus, NGF and depolarization together mediate survival of sympathetic neurons via intracellular convergence on a Ras-PI3-kinase-Akt pathway. This convergent regulation of Akt may provide a general mechanism for coordinating the effects of growth factors and neural activity on neuronal survival throughout the nervous system.

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Related in: MedlinePlus

Proposed models for signal-transduction pathways mediating survival in NGF or KCl alone (a) or synergistically in the presence of both NGF and KCl (b). a, Illustrates the proposed pathways that support sympathetic neuron survival when either NGF or KCl are alone. b, Illustrates the proposed convergence onto the Ras–PI3-kinase–Akt pathway that is essential for the synergistic survival seen at concentrations of NGF and KCl, which on their own are not sufficient for maximal survival.
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Figure 10: Proposed models for signal-transduction pathways mediating survival in NGF or KCl alone (a) or synergistically in the presence of both NGF and KCl (b). a, Illustrates the proposed pathways that support sympathetic neuron survival when either NGF or KCl are alone. b, Illustrates the proposed convergence onto the Ras–PI3-kinase–Akt pathway that is essential for the synergistic survival seen at concentrations of NGF and KCl, which on their own are not sufficient for maximal survival.

Mentions: Data presented here demonstrate that combinations of trophic support (NGF) and neuronal activity (KCl-induced depolarization) have a positive, synergistic effect on the survival of peripheral sympathetic neurons at concentrations of NGF and KCl that are themselves suboptimal for neuronal survival. Moreover, these experiments demonstrate that the synergistic survival is due to convergence onto the PI3-kinase–Akt survival pathway, and that in the case of KCl, activation of this pathway is a consequence of calcium-mediated Ras activation (Fig. 10). In contrast, although KCl-mediated survival also requires concomitant activation of CaMKII, this protein is dispensable when both KCl and NGF are both present (Fig. 10), and it is not involved in activating Akt under any of the conditions studied here. This convergent activation of Akt, a signaling protein known to be essential for the survival of several neuronal populations (Dudek et al. 1997; Crowder and Freeman 1998), may provide a general mechanism for coordinating the survival effects of growth factors and neural activity throughout the developing nervous system.


Depolarization and neurotrophins converge on the phosphatidylinositol 3-kinase-Akt pathway to synergistically regulate neuronal survival.

Vaillant AR, Mazzoni I, Tudan C, Boudreau M, Kaplan DR, Miller FD - J. Cell Biol. (1999)

Proposed models for signal-transduction pathways mediating survival in NGF or KCl alone (a) or synergistically in the presence of both NGF and KCl (b). a, Illustrates the proposed pathways that support sympathetic neuron survival when either NGF or KCl are alone. b, Illustrates the proposed convergence onto the Ras–PI3-kinase–Akt pathway that is essential for the synergistic survival seen at concentrations of NGF and KCl, which on their own are not sufficient for maximal survival.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2169479&req=5

Figure 10: Proposed models for signal-transduction pathways mediating survival in NGF or KCl alone (a) or synergistically in the presence of both NGF and KCl (b). a, Illustrates the proposed pathways that support sympathetic neuron survival when either NGF or KCl are alone. b, Illustrates the proposed convergence onto the Ras–PI3-kinase–Akt pathway that is essential for the synergistic survival seen at concentrations of NGF and KCl, which on their own are not sufficient for maximal survival.
Mentions: Data presented here demonstrate that combinations of trophic support (NGF) and neuronal activity (KCl-induced depolarization) have a positive, synergistic effect on the survival of peripheral sympathetic neurons at concentrations of NGF and KCl that are themselves suboptimal for neuronal survival. Moreover, these experiments demonstrate that the synergistic survival is due to convergence onto the PI3-kinase–Akt survival pathway, and that in the case of KCl, activation of this pathway is a consequence of calcium-mediated Ras activation (Fig. 10). In contrast, although KCl-mediated survival also requires concomitant activation of CaMKII, this protein is dispensable when both KCl and NGF are both present (Fig. 10), and it is not involved in activating Akt under any of the conditions studied here. This convergent activation of Akt, a signaling protein known to be essential for the survival of several neuronal populations (Dudek et al. 1997; Crowder and Freeman 1998), may provide a general mechanism for coordinating the survival effects of growth factors and neural activity throughout the developing nervous system.

Bottom Line: This convergent PI3-kinase-Akt pathway was essential for synergistic survival.In contrast, inhibition of calcium/calmodulin-dependent protein kinase II revealed that, while this molecule was essential for depolarization-induced survival, it had no role in KCl- induced Akt phosphorylation, nor was it important for synergistic survival by NGF and KCl.This convergent regulation of Akt may provide a general mechanism for coordinating the effects of growth factors and neural activity on neuronal survival throughout the nervous system.

View Article: PubMed Central - PubMed

Affiliation: Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4.

ABSTRACT
In this report, we have examined the mechanisms whereby neurotrophins and neural activity coordinately regulate neuronal survival, focussing on sympathetic neurons, which require target-derived NGF and neural activity for survival during development. When sympathetic neurons were maintained in suboptimal concentrations of NGF, coincident depolarization with concentrations of KCl that on their own had no survival effect, synergistically enhanced survival. Biochemical analysis revealed that depolarization was sufficient to activate a Ras-phosphatidylinositol 3-kinase-Akt pathway (Ras-PI3-kinase-Akt), and function-blocking experiments using recombinant adenovirus indicated that this pathway was essential for approximately 50% of depolarization-mediated neuronal survival. At concentrations of NGF and KCl that promoted synergistic survival, these two stimuli converged to promote increased PI3-kinase-dependent Akt phosphorylation. This convergent PI3-kinase-Akt pathway was essential for synergistic survival. In contrast, inhibition of calcium/calmodulin-dependent protein kinase II revealed that, while this molecule was essential for depolarization-induced survival, it had no role in KCl- induced Akt phosphorylation, nor was it important for synergistic survival by NGF and KCl. Thus, NGF and depolarization together mediate survival of sympathetic neurons via intracellular convergence on a Ras-PI3-kinase-Akt pathway. This convergent regulation of Akt may provide a general mechanism for coordinating the effects of growth factors and neural activity on neuronal survival throughout the nervous system.

Show MeSH
Related in: MedlinePlus