Abstract
We have shown marked promotion of both proliferation and neuronal differentiation in pluripotent P19 cells exposed to the green tea amino acid theanine, which is a good substrate for SLC38A1 responsible for glutamine transport. In this study, we evaluated the activity of the mammalian target of rapamycin (mTOR) kinase pathway, which participates in protein translation, cell growth and autophagy in a manner relevant to intracellular glutamine levels, in murine neural progenitor cells exposed to theanine. Exposure to theanine promoted the phosphorylation of mTOR and downstream proteins in neurospheres from embryonic mouse neocortex. Although stable overexpression of SLC38A1 similarly facilitated phosphorylation of mTOR-relevant proteins in undifferentiated P19 cells, theanine failed to additionally accelerate the increased phosphorylation in these stable transfectants. Theanine accelerated the formation of neurospheres from murine embryonic neocortex and adult hippocampus, along with facilitation of both 5-bromo-2’-deoxyuridine incorporation and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide reduction in embryonic neurospheres. In embryonic neurospheres previously exposed to theanine, a significant increase was seen in the number of cells immunoreactive for a neuronal marker protein after spontaneous differentiation. These results suggest that theanine activates the mTOR signaling pathway for proliferation together with accelerated neurogenesis in murine undifferentiated neural progenitor cells.
Highlights
We have shown marked promotion of both proliferation and neuronal differentiation in pluripotent P19 cells exposed to the green tea amino acid theanine, which is a good substrate for SLC38A1 responsible for glutamine transport
The essential importance of the present findings is that the green tea ingredient theanine, which is an amino acid with a structural analog to Gln rather than glutamate, promoted the phosphorylation of intracellular signaling molecules relevant to the mammalian target of rapamycin (mTOR) kinase pathway in cultured neural progenitor cells isolated from embryonic mouse neocortex, in addition to facilitating both activities for proliferation and subsequent neuronal differentiation
The fact that prolonged exposure to theanine increased the size of neurospheres obtained from the hippocampus of adult Nestin-green fluorescent protein (GFP) transgenic mice gives support for the proposal that theanine promotes proliferation for self-replication in adult neurogenesis
Summary
[3H]glutamate uptake in rat brain synaptosomes, while both [3H]theanine and [3H]Gln were taken up in a sodium- and structure-dependent manner [4]. Marked promotion of cellular proliferation and neuronal differentiation was seen in pluripotent P19 cells with stable overexpression of solute carrier 38a1 (SLC38A1 1⁄4 glutamine transporter, GlnT), which is responsible for the membrane transport of Gln in the brain [10] Theanine accelerated both activities in control stable transfectants with empty vector (EV), but failed to further facilitate the promotion of both proliferation and neuronal differentiation activities in stable Slc38a1 transfectants [11]. These previous findings prompted us to investigate the activity of mTOR signaling-related molecules in neural progenitor cells exposed to theanine. We evaluated pharmacological actions of theanine on the proliferation in hippocampal progenitor cells [13] isolated from adult mice with predominant overexpression of green fluorescent protein (GFP) in cells expressing nestin [14]
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