Journal
FASEB JOURNAL
Volume 18, Issue 11, Pages 1544-+Publisher
WILEY
DOI: 10.1096/fj.04-1581fje
Keywords
insulin-like growth factor; dorsal root ganglia neurons; apoptosis; glucose; CREB; FKHR
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Funding
- NHGRI NIH HHS [HG02367] Funding Source: Medline
- NIDDK NIH HHS [DK063340] Funding Source: Medline
- NINDS NIH HHS [NS43023, NS38849, NS36778] Funding Source: Medline
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Insulin-like growth factor-I (IGF-I) protects neurons of the peripheral nervous system from apoptosis, but the underlying signaling pathways are not well understood. We studied IGF-I mediated signaling in embryonic dorsal root ganglia (DRG) neurons. DRG neurons express IGF-I receptors (IGF-IR), and IGF-I activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. High glucose exposure induces apoptosis, which is inhibited by IGF-I through the PI3K/Akt pathway. IGF-I stimulation of the PI3K/Akt pathway phosphorylates three known Akt effectors: the survival transcription factor cyclic AMP response element binding protein ( CREB) and the pro-apoptotic effector proteins glycogen synthase kinase-3 (GSK-3) and forkhead ( FKHR). IGF-I regulates survival at the nuclear level through accumulation of phospho-Akt in DRG neuronal nuclei, increased CREB-mediated transcription, and nuclear exclusion of FKHR. High glucose increases expression of the pro-apoptotic Bcl protein Bim ( a transcriptional target of FKHR). However, IGF-I does not regulate Bim or anti-apoptotic Bcl-xL protein expression levels, which suggests that IGF-I neuroprotection is not through regulation of their expression. High glucose also induces loss of the initiator caspase-9 and increases caspase-3 cleavage, effects blocked by IGF-I. These data suggest that IGF-I prevents apoptosis in DRG neurons by regulating PI3K/Akt pathway effectors, including GSK-3, CREB, and FKHR, and by blocking caspase activation.
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