pH-Dependent Inhibition of Kainate Receptors by Zinc

Abstract

Kainate receptors contribute to synaptic plasticity and rhythmic oscillatory firing of neurons in corticolimbic circuits including hippocampal area CA3. We use zinc chelators and mice deficient in zinc transporters to show that synaptically released zinc inhibits postsynaptic kainate receptors at mossy fiber synapses and limits frequency facilitation of kainate, but not AMPA EPSCs during thetapattern stimulation. Exogenous zinc also inhibits the facilitatory modulation of mossy fiber axon excitability by kainate but does not suppress the depressive effect of kainate on CA3 axons. Recombinant kainate receptors are inhibited in a subunit-dependent manner by physiologically relevant concentrations of zinc, with receptors containing the KA1 subunit being sensitive to submicromolar concentrations of zinc. Zinc inhibition does not alter receptor desensitization nor apparent agonist affinity and is only weakly voltage dependent, which points to an allosteric mechanism. Zinc inhibition is reduced at acidic pH. Thus, in the presence of zinc, a fall in pH potentiates kainate receptors by relieving zinc inhibition. Acidification of the extracellular space, as occurs during repetitive activity, may therefore serve to unmask kainate receptor neurotransmission. We conclude that zinc modulation of kainate receptors serves an important role in shaping kainate neurotransmission in the CA3 region.

Activation of Group I Metabotropic Glutamate Receptors Potentiates Heteromeric Kainate Receptors

“…3E) in the presence of an AMPA receptor inhibitor (GYKI 52466). Second, consistent with the results found by Mott et al (2008), incubation of cortical cultures with 100 mM CNQX significantly reduced the KAR-mediated AMPA-induced calcium transient, whereas a lower, AMPA receptor-specific concentration (1.5 mM) in the presence of GYKI 52466 did not (Fig. 3F).…”

Unraveling the role of zinc in memory

“…They also raise additional questions. For example, zinc regulates a number of postsynaptic targets, including NMDA (2) and kainate receptors (14). Results of this study (8) demonstrate that the effects of zinc on certain cognitive tasks can be explained by a presynaptic effect on Erk signaling.…”

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.…”