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

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 ∼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.

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

“…24,40,42 Membrane depolarization has been shown to activate the PI3K-Akt signaling in neuronal cells. 43,44 Link et al 45 have reported that TRPV2 activity induces membrane depolarization during immune complex-induced phagocytosis. We hypothesized that the influx of Na þ through Trvp5/6 under the low [Ca 2 þ ] condition may lead to membrane depolarization, which in turn increases IGF signaling in these cells.…”

Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

“…39 The kinase activity of Akt is sustained by phosphorylation on Ser-473 by upstream kinases. This site is rapidly dephosphorylated after the induction of apoptosis by potassium deprivation.…”

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

“…Akt (also known as protein kinase B) is a serine/threonine protein kinase that transduces intracellular anti-apoptotic signals that are mediated by serum or growth factors that activate phosphoinositide 3-kinase, or PI3-kinase (Franke et al, 1995;Datta et al, 1997;Dudek et al, 1997;Kennedy et al, 1997;Coffer et al, 1998;Downward 1998;Nunez and del Peso, 1998;Goswami et al, 1999;Kennedy et al, 1999;Flores et al, 2000). Overexpression of Akt prevents apoptosis in certain cells, including neurons, following withdrawal of serum or growth factors (Yao and Cooper, 1995;Datta et al, 1997;Dudek et al, 1997;Crowder and Freeman, 1998;Eves et al, 1998;Ulrich et al, 1998;Bhave et al, 1999;Vaillant et al, 1999;Virdee et al, 1999;Flores et al, 2000;Kermer et al, 2000). The precise mechanisms by which Akt promotes cell survival are not entirely clear.…”