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.
Besser
Limor
L
Department of Morphology, Ben Gurion University, Beer-Sheva 84105, Israel.
Chorin
Ehud
E
Sekler
Israel
I
Silverman
William F
WF
Atkin
Stan
S
Russell
James T
JT
Hershfinkel
Michal
M
D000818:Animals; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D019599:Mossy Fibers, Hippocampal / Q000502:physiology; D009474:Neurons / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism* / Q000502:physiology*
D004791:Enzyme Inhibitors; C512928:GPR39 protein, mouse; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D019284:Thapsigargin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D020928:Mitogen-Activated Protein Kinases; D015032:Zinc