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The Journal of Neuroscience, February 13, 2008, 28(7):1659-1671; doi:10.1523/JNEUROSCI.3567-07.2008

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Cellular/Molecular
pH-Dependent Inhibition of Kainate Receptors by Zinc

David D. Mott,¹ Morris Benveniste,² and Raymond J. Dingledine³

¹Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina 29208, ²Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia 30310, and ³Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322

Correspondence should be addressed to Dr. David D. Mott, Department of Pharmacology, Physiology, and Neuroscience, School of Medicine, University of South Carolina, Columbia, SC 29208. Email: dmott{at}med.sc.edu

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 theta-pattern 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.

Key words: zinc; kainate receptor; CA3; glutamate receptor; mossy fiber; hippocampus; pH

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Received Aug. 6, 2007; revised Jan. 1, 2008; accepted Jan. 5, 2008.

Correspondence should be addressed to Dr. David D. Mott, Department of Pharmacology, Physiology, and Neuroscience, School of Medicine, University of South Carolina, Columbia, SC 29208. Email: dmott{at}med.sc.edu

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