title: Upregulation of KCC2 activity by zinc-mediated neurotransmission via the mZnR/GPR39 receptor.
abstract: Vesicular Zn(2+) regulates postsynaptic neuronal excitability upon its corelease with glutamate. We previously demonstrated that synaptic Zn(2+) acts via a distinct metabotropic zinc-sensing receptor (mZnR) in neurons to trigger Ca(2+) responses in the hippocampus. Here, we show that physiological activation of mZnR signaling induces enhanced K(+)/Cl(-) cotransporter 2 (KCC2) activity and surface expression. As KCC2 is the major Cl(-) outward transporter in neurons, Zn(2+) also triggers a pronounced hyperpolarizing shift in the GABA(A) reversal potential. Mossy fiber stimulation-dependent upregulation of KCC2 activity is eliminated in slices from Zn(2+) transporter 3-deficient animals, which lack synaptic Zn(2+). Importantly, activity-dependent ZnR signaling and subsequent enhancement of KCC2 activity are also absent in slices from mice lacking the G-protein-coupled receptor GPR39, identifying this protein as the functional neuronal mZnR. Our work elucidates a fundamentally important role for synaptically released Zn(2+) acting as a neurotransmitter signal via activation of a mZnR to increase Cl(-) transport, thereby enhancing inhibitory tone in postsynaptic cells.
authors: Department of Morphology, Faculty of Health Sciences and The Zlotowski Center of Neuroscience, Ben-Gurion University, Beer-Sheva, 84015, Israel.
authors: Ehud
authors: E
authors: Chorin
authors: Ofir
authors: O
authors: Vinograd
authors: Ilya
authors: I
authors: Fleidervish
authors: David
authors: D
authors: Gilad
authors: Sharon
authors: S
authors: Herrmann
authors: Israel
authors: I
authors: Sekler
authors: Elias
authors: E
authors: Aizenman
authors: Michal
authors: M
authors: Hershfinkel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000502:physiology; D055724:Electrophysiological Phenomena; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D005838:Genotype; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D019599:Mossy Fibers, Hippocampal / Q000502:physiology; D018408:Patch-Clamp Techniques; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000235:genetics; D011963:Receptors, GABA-A / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters / Q000096:biosynthesis* / Q000502:physiology; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology*; D000096922:K Cl- Cotransporters
chemical_list: D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A; D027981:Symporters; D015032:Zinc; D000096922:K Cl- Cotransporters; C512928:GPR39 protein, mouse