title: Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures.
abstract: The aim of this study was to investigate the role of the synaptic metabotropic zinc receptor mZnR/GPR39 in physiological adaptation to epileptic seizures. We previously demonstrated that synaptic activation of mZnR/GPR39 enhances inhibitory drive in the hippocampus by upregulating neuronal K(+)/Cl(-) co-transporter 2 (KCC2) activity. Here, we first show that mZnR/GPR39 knockout (KO) adult mice have dramatically enhanced susceptibility to seizures triggered by a single intraperitoneal injection of kainic acid, when compared to wild type (WT) littermates. Kainate also substantially enhances seizure-associated gamma oscillatory activity in juvenile mZnR/GPR39 KO hippocampal slices, a phenomenon that can be reproduced in WT tissue by extracellular Zn(2+) chelation. Importantly, kainate-induced synaptic Zn(2+) release enhances surface expression and transport activity of KCC2 in WT, but not mZnR/GPR39 KO hippocampal neurons. Kainate-dependent upregulation of KCC2 requires mZnR/GPR39 activation of the Gαq/phospholipase C/extracellular regulated kinase (ERK1/2) signaling cascade. We suggest that mZnR/GPR39-dependent upregulation of KCC2 activity provides homeostatic adaptation to an excitotoxic stimulus by increasing inhibition. As such, mZnR/GPR39 may provide a novel pharmacological target for dampening epileptic seizure activity.
authors.affiliation: Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Faculty of Health Sciences, Beer-Sheva, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Gilad
authors.affiliation: Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Faculty of Health Sciences, Beer-Sheva, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shorer
authors.affiliation: Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Faculty of Health Sciences, Beer-Sheva, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Ketzef
authors.affiliation: Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Faculty of Health Sciences, Beer-Sheva, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Friedman
authors.affiliation: Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Faculty of Health Sciences, Beer-Sheva, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Sekler
authors.affiliation: Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Faculty of Health Sciences, Beer-Sheva, Israel; Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Aizenman
authors.affiliation: Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Faculty of Health Sciences, Beer-Sheva, Israel. Electronic address: hmichal@bgu.ac.il.
authors.forename: Michal
authors.initials: M
authors.lastname: Hershfinkel
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004492:Edetic Acid / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005452:Fluoresceins / Q000378:metabolism; D065818:Gamma Rhythm / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics*; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced* / Q000473:pathology; D018709:Statistics, Nonparametric; D027981:Symporters / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D004492:Edetic Acid; D018690:Excitatory Amino Acid Agonists; D005452:Fluoresceins; D007608:Kainic Acid; D043562:Receptors, G-Protein-Coupled; D027981:Symporters; D015032:Zinc; D000096922:K Cl- Cotransporters; C509804:Gpr37 protein, mouse; C501987:zinpyr-1
keywords: Epilepsy; Hippocampus; KCC2; Kainic acid; Seizure; Zinc receptor; mZnR/GPR39