title: A role for intracellular zinc in glioma alteration of neuronal chloride equilibrium.
abstract: Glioma patients commonly suffer from epileptic seizures. However, the mechanisms of glioma-associated epilepsy are far to be completely understood. Using glioma-neurons co-cultures, we found that tumor cells are able to deeply influence neuronal chloride homeostasis, by depolarizing the reversal potential of γ-aminobutyric acid (GABA)-evoked currents (EGABA). EGABA depolarizing shift is due to zinc-dependent reduction of neuronal KCC2 activity and requires glutamate release from glioma cells. Consistently, intracellular zinc loading rapidly depolarizes EGABA in mouse hippocampal neurons, through the Src/Trk pathway and this effect is promptly reverted upon zinc chelation. This study provides a possible molecular mechanism linking glioma invasion to excitation/inhibition imbalance and epileptic seizures, through the zinc-mediated disruption of neuronal chloride homeostasis.
authors.affiliation: 1] Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Piazzale Aldo Moro 5, Roma 00185, Italy [2] Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Roma 00161, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Di Angelantonio
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Piazzale Aldo Moro 5, Roma 00185, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Murana
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Piazzale Aldo Moro 5, Roma 00185, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cocco
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Piazzale Aldo Moro 5, Roma 00185, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Scala
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Piazzale Aldo Moro 5, Roma 00185, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bertollini
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Piazzale Aldo Moro 5, Roma 00185, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Molinari
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Piazzale Aldo Moro 5, Roma 00185, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Lauro
authors.affiliation: INSERM URM 1106, Aix-Marseille University, Brain Dynamics Institute, Marseille, France.
authors.forename: P
authors.initials: P
authors.lastname: Bregestovski
authors.affiliation: 1] Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Piazzale Aldo Moro 5, Roma 00185, Italy [2] IRCCS Neuromed, Via Atinese, Pozzilli, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Limatola
authors.affiliation: 1] Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Piazzale Aldo Moro 5, Roma 00185, Italy [2] IRCCS Neuromed, Via Atinese, Pozzilli, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Ragozzino
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D018920:Coculture Techniques; D005260:Female; D005910:Glioma / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D002712:Chlorides; D005971:Glutamates; D026901:Membrane Transport Proteins; D020813:Receptor, trkB; D027981:Symporters; D015032:Zinc; D005680:gamma-Aminobutyric Acid; D019061:src-Family Kinases; D000096922:K Cl- Cotransporters