Phosphatidylinositol 3‐kinase and Akt effectors mediate insulin‐like growth factor‐I neuroprotection in dorsal root ganglia neurons

Abstract

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‐3β (GSK‐3β) 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‐3β, CREB, and FKHR, and by blocking caspase activation.