Synaptically released zinc triggers metabotropic signaling via a zinc-sensing receptor in the hippocampus

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.