@article {Besser2890, author = {Limor Besser and Ehud Chorin and Israel Sekler and William F. Silverman and Stan Atkin and James T. Russell and Michal Hershfinkel}, title = {Synaptically Released Zinc Triggers Metabotropic Signaling via a Zinc-Sensing Receptor in the Hippocampus}, volume = {29}, number = {9}, pages = {2890--2901}, year = {2009}, doi = {10.1523/JNEUROSCI.5093-08.2009}, publisher = {Society for Neuroscience}, abstract = {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.}, issn = {0270-6474}, URL = {https://www.jneurosci.org/content/29/9/2890}, eprint = {https://www.jneurosci.org/content/29/9/2890.full.pdf}, journal = {Journal of Neuroscience} }