Synaptically Released Zinc Triggers Metabotropic Signaling via a Zinc-Sensing Receptor in the Hippocampus

Abstract

Summary Zn2+ that is co-released with glutamate from mossy fiber terminals can influence synaptic function. Here, we demonstrate that synaptically released Zn2+ activates a selective post-synaptic 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. ZnR-mediated Ca2+ rises were dramatically attenuated in slices from mice lacking vesicular Zn2+. In addition, knockdown of the expression of the orphan G-protein coupled receptor 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.

Redox Regulation of Intracellular Zinc: Molecular Signaling in the Life and Death of Neurons

“…Zn 2þ inhibits N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid receptor subtypes, and potentiates glycine receptors (96,110). In addition to modulating ionotropic pathways, synaptic Zn 2þ has also been reported to transactivate receptor tyrosine kinase b (42) and regulate metabotropic activity through the activation of a recently described Zn 2þ receptor, ZnR (10). Of interest, the molecular identity of the ZnR has been proposed to be the orphan G protein-linked receptor GPR39 (10).…”

“…In addition to modulating ionotropic pathways, synaptic Zn 2þ has also been reported to transactivate receptor tyrosine kinase b (42) and regulate metabotropic activity through the activation of a recently described Zn 2þ receptor, ZnR (10). Of interest, the molecular identity of the ZnR has been proposed to be the orphan G protein-linked receptor GPR39 (10). However, since the exact magnitude and time course of synaptic Zn 2þ remain unclear (47), the full range of physiological roles for vesicular Zn 2þ has yet to be fully described.…”

Vesicular Zinc Regulates the Ca2+Sensitivity of a Subpopulation of Presynaptic Vesicles at Hippocampal Mossy Fiber Terminals

“…Exocytosis of zinc during synaptic activity has been convincingly demonstrated (Kay, 2003;Qian and Noebels, 2005), but its actual release into the synaptic cleft and hence its regulatory role in postsynaptic functions remains controversial (Kay and Tó th, 2008;Paoletti et al, 2009;Tó th, 2011). Studies that have examined the physiological role of vesicular zinc mainly focused on its possible involvement in postsynaptic regulation (Vogt et al, 2000;Molnár and Nadler, 2001;Lopantsev et al, 2003;Mott et al, 2008;Besser et al, 2009), whereas its regulatory role in presynaptic release mechanisms remains unexplored.…”

Unraveling the role of zinc in memory

“…Furthermore, zinc can activate Erk in neurons (10), raising the possibility that zinc could influence learning and memory by acting on the Erk signaling pathway. However, earlier studies examining the interaction between zinc and Erk had used exogenously applied zinc, making it unclear whether synaptically released zinc acted as an endogenous regulator of Erk.…”