Upregulation of KCC2 activity by zinc-mediated neurotransmission via the mZnR/GPR39 receptor

Ehud Chorin, Ofir Vinograd, Ilya Fleidervish, David Gilad, Sharon Herrmann, Israel Sekler, Elias Aizenman, Michal Hershfinkel

Research output: Contribution to journalArticlepeer-review

118 Scopus citations


Vesicular Zn2+ regulates postsynaptic neuronal excitability upon its corelease with glutamate. We previously demonstrated that synaptic Zn2+ acts via a distinct metabotropic zinc-sensing receptor (mZnR) in neurons to trigger Ca2+ responses in the hippocampus. Here, we show that physiological activation of mZnR signaling induces enhanced K+/Cl-cotransporter 2 (KCC2) activity and surface expression. As KCC2 is the major Cl-outward transporter in neurons, Zn2+ also triggers a pronounced hyperpolarizing shift in the GABAA reversal potential. Mossy fiber stimulation-dependent upregulation of KCC2 activity is eliminated in slices from Zn2+ transporter 3-deficient animals, which lack synaptic Zn2+. Importantly, activity-dependent ZnR signaling and subsequent enhancement of KCC2 activity are also absent in slices from mice lacking the G-protein-coupled receptor GPR39, identifying this protein as the functional neuronal mZnR. Our work elucidates a fundamentally important role for synaptically released Zn2+ acting as a neurotransmitter signal via activation of a mZnR to increase Cl-transport, thereby enhancing inhibitory tone in postsynaptic cells.

Original languageEnglish
Pages (from-to)12916-12926
Number of pages11
JournalJournal of Neuroscience
Issue number36
StatePublished - 7 Sep 2011

ASJC Scopus subject areas

  • General Neuroscience


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