Abstract
Glycogen synthase kinases-3β (GSK3β) is a key regulator of cell homeostasis. In neurons, GSK3β contributes to control of neuronal transmission and plasticity. Despite extensive studies in non-neuronal cells, crosstalk between GSK3β and other signaling pathways remains not well defined in neurons. In the present study, we report that GSK3β positively affected the activity of effectors of mammalian target of rapamycin complex 1 (mTORC1) and complex 2 (mTORC2), in mature neurons in vitro and in vivo. GSK3β also promoted prosurvival signaling and attenuated kainic acid-induced apoptosis. Our study identified GSK3β as a positive regulator of prosurvival signaling, including the mTOR pathway, and indicates the possible neuroprotective role of GSK3β in models of pharmacologically induced excitotoxicity.
Highlights
The glycogen synthase kinase-3 (GSK3) family of protein kinases is crucially important for cell metabolism and homeostasis [1, 2]
BIO was more potent and in most cases, degree of the inhibition reached statistical significance (Fig. 2a–d). These results indicated that GSK3α and Glycogen synthase kinases-3β (GSK3β) were needed to sustain the physiological activity of mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 under basal conditions
To confirm that the observed positive impact of GSK3β on mTORC1 and mTORC2 effectors was not restricted to cultured neurons, we examined the way in which this kinase affects their phosphorylation in the brain in vivo
Summary
The glycogen synthase kinase-3 (GSK3) family of protein kinases is crucially important for cell metabolism and homeostasis [1, 2]. Two genes encode GSK3 proteins: GSK3α and GSK3β. GSK3α and GSK3β are structurally similar with partially overlapping substrate specificity and cellular functions, these remain ill defined [1, 2]. Among the downstream effectors of GSK3α and GSK3β are mammalian target of rapamycin (mTOR) complexes 1 and 2 (mTORC1 and mTORC2), key regulators of cell metabolism and the cytoskeleton [3]. Several molecular pathways that underlie the GSK3 isozyme-dependent inhibition of mTOR have been described [4, 5] but in some cases, GSK3α and GSK3β were shown to positively regulate the mTORC1 pathway, e.g. MCF7 and neuroblastoma SHSY5Y [6,7,8]. Unknown to date is whether such positive regulation occurs only in selected cell lines or may exist in highly differentiated cells, such as neurons
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