Zn 2+ is coreleased with glutamate from mossy fiber terminals and can influence synaptic function. Here, we demonstrate that synaptically released Zn 2+ activates a selective postsynaptic Zn 2+-sensing receptor (ZnR) in the CA3 region of the hippocampus. ZnR activation induced intracellular release of Ca 2+, as well as phosphorylation of extracellular-regulated kinase and Ca 2+/calmodulin kinase II. Blockade of synaptic transmission by tetrodotoxin or CdCl inhibited the ZnR-mediated Ca 2+ rises. The responses mediated by ZnR were largely attenuated by the extracellular Zn 2+ chelator, CaEDTA, and in slices from mice lacking vesicular Zn 2+, suggesting that synaptically released Zn 2+ 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 Zn 2+ acting as the physiological ligand of a metabotropic receptor and provide a novel pathway by which synaptic Zn 2+ can regulate neuronal function.
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