JCB logo
Accuri Cytometers
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article
Right arrow Full Text
Right arrow Full Text (PDF, 792K)
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JCB
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vaillant, A.R.
Right arrow Articles by Miller, F.D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vaillant, A.R.
Right arrow Articles by Miller, F.D.
Social Bookmarking
 Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
© The Rockefeller University Press, 0021-9525/1999/9/955/ $5.00
The Journal of Cell Biology, Volume 146, Number 5, September 6, 1999 955-966

Depolarization and Neurotrophins Converge on the Phosphatidylinositol 3-Kinase–Akt Pathway to Synergistically Regulate Neuronal Survival

A.R. Vaillanta, I. Mazzonia,b, C. Tudanb, M. Boudreaua,b, D.R. Kaplana,b, and F.D. Millera
a Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4
b Brain Tumor Research Center, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4

Correspondence to: F.D. Miller, Center for Neuronal Survival, Montreal Neurological Institute, McGill University, 3801 rue University, Montreal, Quebec, Canada H3A 2B4. Tel:(514) 398-4261 Fax:(514) 398-1319 E-mail:mdfm{at}musica.mcgill.ca.

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 ~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.

Key Words: nerve growth factor, sympathetic, neurons, ras, mitogen-activated protein kinase, calcium/calmodulin-dependent protein kinase II


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents