The neuronal function of Cys-loop neurotransmitter receptors is established; however, their role in non-neuronal cells is poorly defined. As brain tumors are enriched in the neurotransmitter glycine, we studied the expression and function of glycine receptors (GlyRs) in glioma cells. Human brain tumor biopsies selectively expressed the GlyR alpha 1 and alpha 3 subunits, which have nuclear localization signals (NLSs). The mouse glioma cell line GL261 expressed GlyR alpha 1, and knockdown of GlyR alpha 1 protein expression impaired the self-renewal capacity and tumorigenicity of GL261 glioma cells, as shown by a neurosphere assay and GL261 cell inoculation in vivo, respectively. We furthermore showed that the pronounced tumorigenic effect of GlyR alpha 1 relies on a new intracellular signaling function that depends on the NLS region in the large cytosolic loop and impacts on GL261 glioma cell gene regulation. Stable expression of GlyR alpha 1 and alpha 3 loops rescued the self-renewal capacity of GlyR alpha 1 knockdown cells, which demonstrates their functional equivalence. The new intracellular signaling function identified here goes beyond the well-established role of GlyRs as neuronal ligand-gated ion channels and defines NLS-containing GlyRs as new potential targets for brain tumor therapies.
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