bFGF promotes photoreceptor cell survival in vitro by PKA‐mediated inactivation of glycogen synthase kinase 3β and CREB‐dependent Bcl‐2 up‐regulation

Abstract

Although there is substantial evidence supporting the neuroprotective efficacy of basic fibroblast growth factor (bFGF) in the rodent retina there is no consensus to date as to the protective mechanism involved. We hypothesise that bFGF can assert its neuroprotective effects directly on mouse photoreceptors transduced via the activation of specific intracellular signalling pathways. In mouse photoreceptor-derived 661W cells, bFGF promoted a rapid inactivation of glycogen synthase kinase 3b (GSK3b) by phosphorylation at Ser9.The effects of bFGF on GSK3b were dependent on protein kinase A (PKA) activation, as inhibition of this pathway blocked inactivation. Furthermore, bFGF protection against oxidative stress was dependent on PKA inactivation of GSK3b as PKA inhibition attenuated bFGF-induced protection. Furthermore, transfection of cells with mutant dominant negative GSK3bS9A that cannot be phosphorylated on Ser9 also abrogated neuroprotection. Activation of the transcription factor cAMP-response element binding protein (CREB) and subsequent up-regulation of Bcl-2 in response to bFGF was also dependent on PKA as inhibition with H-89 attenuated increased pCREB levels and Bcl-2 expression. These results indicate that the protective efficacy of bFGF in mouse photoreceptors involves PKA-dependent inactivation of GSK3b and subsequent up-regulation of Bcl-2 via CREB activation.

Differential Roles of Epac in Regulating Cell Death in Neuronal and Myocardial Cells

“…In neuronal cells activation of cAMP/PKA signaling inhibited apoptosis induced by KCl in cerebella granule neurons (42) or by human immunodeficiency virus protein gp120 in the brain (43), promoting survival pathways in multiple neuronal cells (44,45); these findings are in agreement with ours (supplemental Fig. 4).…”

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

“…Alternatively, Syk inhibition may also result in a suppression of NFB activation via an inhibition of RAF phosphorylation and AKT phosphorylation, which consequently is expected to lower BACE-1 expression and A␤ production. Interestingly, we show that Syk inhibition results in a stimulation of CREB phosphorylation via PKA activation suggesting that Syk inhibition could also have neuroprotective properties because stimulation of CREB phosphorylation by PKA is known to confer neuroprotection (73)(74)(75). Also, PKA and CREB phosphorylation are down-regulated in AD brains (76) and in transgenic mouse models of AD overexpressing A␤, whereas stimulation of PKA/ CREB phosphorylation with various compounds improves memory in AD mouse models (77)(78)(79)(80) suggesting that Syk inhibition has the potential to reduce memory impairments by stimulating PKA/CREB signaling.…”

Leukemia Inhibitory Factor Extends the Lifespan of Injured PhotoreceptorsIn Vivo

“…Rattner and Nathans (2005) recently proposed a specific retinal response to injury which involves the production and secretion of Edn2 by injured photoreceptors leading to the activation of Muller glia cells via Ednrb and to an increased expression of FGF2. FGF2 is a potent neurotrophic factor that is upregulated in various situations of retinal stress (Gao and Hollyfield, 1996;Hackett et al, 1997;Grimm et al, 2002) and that can protect retinal cells against various insults (Unoki and LaVail, 1994;Liu et al, 1998;Yamada et al, 2001;Schuettauf et al, 2004;O'Driscoll et al, 2007O'Driscoll et al, , 2008. Intriguingly, this response seems not to be initiated by the damaged photoreceptors themselves but rather by a specific subset of Muller glia cells which react with the expression of LIF to photoreceptor injury (Fig.…”