Hypoinsulinemia Alleviates the Grf1/Ras/Akt Anti-Apoptotic Pathway and Induces Alterations of Mitochondrial Ras Trafficking in Neuronal Cells

Abstract

Recent observations have established that interruption of insulin production causes deficits in learning and memory formation. We have studied the mechanism of insulin's neuroprotective effect on primary neuronal cells and in streptozotocin (STZ)-induced diabetic rat brain. We have found that in hippocampal neuronal cells insulin increases the content of farnesylated Ras and phosphorylated form of Akt. Besides, the treatment of cells by insulin leads to the activation of mitochondrial cytochrome oxidase, which is inhibited by manumycin, a farnesyltransferase inhibitor. During experimental diabetes, the content of membrane-bound GRF1 was decreased in rat hippocampus that was correlated with the reduction in mitochondrial Ras and phosphorylated forms of Akt. This redistribution in Ras-GRF system was accompanied by the alteration in the activities of CREB, NF-kB (p65) and c-Rel transcription factors. We have proposed that hypoinsulinemia induces the inhibition of Ras signalling in the neuronal cells additionally by abnormality of Ras trafficking into mitochondria.

Insulin in the Brain: Sources, Localization and Functions

“…Moreover, a positive correlation between elevated neuronal apoptosis in type 1 diabetes and reduced expression of insulin and IGF receptors may also exist [272]. Zhuravliova et al [273] reported that hypoinsulinemia causes regulatory proteins to be redistributed between intracellular compartments. For instance, the content of Grf1 bound to membrane and mitochondrial Ras are reduced in response to hypoinsulinemia.…”

“…Ras is the mediator of Akt activation by PI3K that eventually induces phosphorylation of various proteins such as mitochondrial antiapoptotic proteins. So, Ras inhibition by insulin deficiencies is thought to promote neuronal apoptosis [273]. Baek et al have also reported that insulin withdrawal from HCN cells derived from adult rat brain induces autophagic cell death [274].…”

diffReps: Detecting Differential Chromatin Modification Sites from ChIP-seq Data with Biological Replicates

“…RASGRF1 is induced by cocaine, which promotes Ras-Mapk signaling in the nucleus accumbens [25] and is important for phospho-CREB signaling [26] and ΔFosB accumulation [27], both of which are important for cocaine behavior.…”

Insulin Neuroprotection and the Mechanisms

“…[ 9 ] Insulin partially protected against glutamate decreased cell viability in cultured neuronal cells. [ 10 11 ] Fanne et al . found, insulin decreased glutamate levels in the cerebral spinal fluid of rats, decreased infarct size and improved neuro-scoring.…”