Abstract
Collapsin response mediator protein (CRMP)-2 and the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway are associated with common physiological functions such as neuronal polarity, axonal outgrowth and synaptic strength, as well as various brain disorders including epilepsy. But, their regulatory and functional links are unclear. Alterations in CRMP-2 expression that lead to its functional changes are implicated in brain disorders such as epilepsy. Here, we investigate whether changes in CRMP-2 expression, possibly regulated by mTOR-related signaling, correlates with neuronal growth and viability. Inhibition of mTOR and/or phosphoinositol-3-kinase (PI3K) led to deceased p-S6K, and p-S6 signals also reduced CRMP-2 expression. These changes corresponded to inhibition of neuronal viability and proliferation in cultured hippocampal HT-22 cells under both basal serum-free and serum- or insulin-induced mTOR pathway-activated conditions. CRMP-2 expression tended to be increased by mTOR activation, indicated by an increase in p-S6/S6 level, in pentylentetrazole (PTZ)-induced epileptic rat hippocampal tissues was also significantly reduced by mTOR inhibition. Knockdown of CRMP-2 by si-RNA reduced the neuronal viability without changes in mTOR signaling, and overexpression of CRMP-2 recovered the glutamate-induced neurotoxicity and decrease of mTOR signaling in HT-22 cells. In conclusion, CRMP-2 protein expression controlled by the PI3K-mTOR-S6K signaling axis exerts its important functional roles in neuronal growth and survival.
Highlights
Collapsin response mediator protein-2 (CRMP-2) is widely expressed in the central nervous system (CNS), and its critical functional involvement in axonal neurite promotion and neuronal polarity through direct or indirect interaction with cytoskeleton molecules such as tubulins has long been demonstrated (Fukada et al, 2000; Charrier et al, 2003)
Rapamycin pretreatment significantly reduced the levels of CRMP-2 and synapsin-I proteins enhanced in the PTZ-treated rat hippocampal tissues (Figures 7F,G). These findings demonstrate that Mammalian target of rapamycin (mTOR) pathways could control CRMP-2 expression and synaptic activity in PTZ-induced epileptic rat brain tissues, similar to that observed in cultured neuronal cells, implicating the potentially important role of CRMP-2 regulated by mTOR in epilepsy, significant changes by rapamycin in the PTZ-induced behavioral seizure activity were not observed in this study
This study presents the link between CRMP-2 and the mTOR signaling pathway, both of which are commonly associated with various physiological and pathological conditions
Summary
Collapsin response mediator protein-2 (CRMP-2) is widely expressed in the central nervous system (CNS), and its critical functional involvement in axonal neurite promotion and neuronal polarity through direct or indirect interaction with cytoskeleton molecules such as tubulins has long been demonstrated (Fukada et al, 2000; Charrier et al, 2003). Mammalian target of rapamycin (mTOR), a serine-threonine protein kinase of the phosphatidylinositol 3-kinase (PI3K)related kinase family (Wullschleger et al, 2006), is a master regulator that integrating energy, nutrients, and other multiple upstream signals to regulate numerous important physiological functions including cell growth, survival, homeostasis, and tissue regeneration and repair (Dazert and Hall, 2011; Zoncu et al, 2011; Laplante and Sabatini, 2012). Both are associated with a number of diseases those including neurodegeneration (Dazert and Hall, 2011; Zoncu et al, 2011; Laplante and Sabatini, 2012) Various ligands such as growth factors and neurotransmitters activate target membrane receptors, and transduce the activated signal, resulting in the modulation of a pathway involving PI3K and Akt, which plays vital roles in cell growth, proliferation, neuroplasticity, and survival (Read and Gorman, 2009). Activation of S6K by mTOR is followed by phosphorylation of a downstream ribosomal protein, S6, at serine 235/236, an alternative marker for mTOR activity, to promote protein translation (Fingar et al, 2004; Hay and Sonenberg, 2004)
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