PT  - JOURNAL ARTICLE
AU  - Besser, Limor
AU  - Chorin, Ehud
AU  - Sekler, Israel
AU  - Silverman, William F.
AU  - Atkin, Stan
AU  - Russell, James T.
AU  - Hershfinkel, Michal
TI  - Synaptically Released Zinc Triggers Metabotropic Signaling via a Zinc-Sensing Receptor in the Hippocampus
AID  - 10.1523/JNEUROSCI.5093-08.2009
DP  - 2009 Mar 04
TA  - The Journal of Neuroscience
PG  - 2890--2901
VI  - 29
IP  - 9
4099  - http://www.jneurosci.org/content/29/9/2890.short
4100  - http://www.jneurosci.org/content/29/9/2890.full
SO  - J. Neurosci.2009 Mar 04; 29
AB  - 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.