title: Intracellular glycine receptor function facilitates glioma formation in vivo.
abstract: 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 α1 and α3 subunits, which have nuclear localization signals (NLSs). The mouse glioma cell line GL261 expressed GlyR α1, and knockdown of GlyR α1 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 α1 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 α1 and α3 loops rescued the self-renewal capacity of GlyR α1 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.
authors.affiliation: RNA editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Förstera
authors.affiliation: Cellular Neuroscience, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.
authors.forename: Omar
authors.initials: O
authors.lastname: Dzaye
authors.affiliation: RNA editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany FU-Berlin, Fachbereich Biologie, Chemie, Pharmazie, Takustrasse 3, 14195 Berlin.
authors.forename: Aline
authors.initials: A
authors.lastname: Winkelmann
authors.affiliation: RNA editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Semtner
authors.affiliation: Department for Physiology, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Bruno
authors.initials: B
authors.lastname: Benedetti
authors.affiliation: Department for Neurosurgery, Helios Clinic Buch, 13125 Berlin, Germany.
authors.forename: Darko S
authors.initials: DS
authors.lastname: Markovic
authors.affiliation: Department for Neurosurgery, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Synowitz
authors.affiliation: David Geffen School of Medicine at UCLA, UCLA Jonsson Comprehensive Cancer Center, 10833 LeConte Avenue, CHS 27-139, Los Angeles, CA. 90095, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wend
authors.affiliation: Institut für Vegetative Physiologie, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fähling
authors.affiliation: INSERM U894, Psychiatry and Neuroscience Center, Glial Plasticity Team, Paris 75014, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Junier
authors.affiliation: Neurosurgical Research, University Clinics Munich, 81377 München, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Glass
authors.affiliation: Cellular Neuroscience, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Kettenmann
authors.affiliation: RNA editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany jochen.meier@mdc-berlin.de.
authors.forename: Jochen C
authors.initials: JC
authors.lastname: Meier
mesh_terms: D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D005998:Glycine / Q000378:metabolism; D006801:Humans; D051379:Mice; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D018009:Receptors, Glycine; D005998:Glycine
keywords: Gene regulation; Glioma; Glycine receptor