Abstract

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 GABA_A 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.