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The Journal of Neuroscience, March 4, 2009, 29(9):2890-2901; doi:10.1523/JNEUROSCI.5093-08.2009

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Cellular/Molecular
Synaptically Released Zinc Triggers Metabotropic Signaling via a Zinc-Sensing Receptor in the Hippocampus

Limor Besser,^1,3 * Ehud Chorin,^1,3 * Israel Sekler,^2,3 William F. Silverman,^1,3 Stan Atkin,⁴ James T. Russell,⁴ and Michal Hershfinkel^1,3

Departments of ¹Morphology and ²Physiology and ³Zlotowski Center, Ben Gurion University, Beer-Sheva 84105, Israel, and ⁴Section for Cell Biology and Signal Transduction, National Institute of Child Health and Human Development–National Institutes of Health, Bethesda, Maryland 20892-4480

Correspondence should be addressed to Michal Hershfinkel, Department of Morphology, Faculty of Health Sciences, Ben Gurion University, P.O. Box 653, Beer-Sheva 84105, Israel. Email: hmichal{at}bgu.ac.il

Zn²⁺ is coreleased with glutamate from mossy fiber terminals and can influence synaptic function. Here, we demonstrate that synaptically released Zn²⁺ activates a selective postsynaptic Zn²⁺-sensing receptor (ZnR) in the CA3 region of the hippocampus. ZnR activation induced intracellular release of Ca²⁺, as well as phosphorylation of extracellular-regulated kinase and Ca²⁺/calmodulin kinase II. Blockade of synaptic transmission by tetrodotoxin or CdCl inhibited the ZnR-mediated Ca²⁺ rises. The responses mediated by ZnR were largely attenuated by the extracellular Zn²⁺ chelator, CaEDTA, and in slices from mice lacking vesicular Zn²⁺, suggesting that synaptically released Zn²⁺ triggers the metabotropic activity. Knockdown of the expression of the orphan G-protein-coupled receptor 39 (GPR39) attenuated ZnR activity in a neuronal cell line. Importantly, we observed widespread GPR39 labeling in CA3 neurons, suggesting a role for this receptor in mediating ZnR signaling in the hippocampus. Our results describe a unique role for synaptic Zn²⁺ acting as the physiological ligand of a metabotropic receptor and provide a novel pathway by which synaptic Zn²⁺ can regulate neuronal function.

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Received Oct. 22, 2008; revised Dec. 23, 2008; accepted Dec. 26, 2008.

Correspondence should be addressed to Michal Hershfinkel, Department of Morphology, Faculty of Health Sciences, Ben Gurion University, P.O. Box 653, Beer-Sheva 84105, Israel. Email: hmichal{at}bgu.ac.il

eLetters:

Read all eLetters

The Origin of Zinc

Katalin Toth

J. Neurosci. Online, 16 Mar 2009 [Full text]

Re: The Origin of Zinc

Michal Hershfinkel

J. Neurosci. Online, 29 Mar 2009 [Full text]

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