pH-Dependent inhibition of kainate receptors by zinc

• Type of Material: Article
• Authors: David D. Mott, University of South Carolina; Morris Benveniste, Morehouse School of Medicine; Raymond J Dingledine, Emory University
• Language: English
• Date: 2008-02-13
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2008 Society for Neuroscience.
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.3567-07.2008
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0888-0395
• Volume: 28
• Issue: 7
• Start Page: 1659
• End Page: 1671
• Grant/Funding Information: This work was supported by the Epilepsy Foundation (D.M.); National Alliance for Research on Schizophrenia and Depression (D.M.); the University Research Council of Emory University (D.M.); National Institute of Neurological Disorders and Stroke (R.D.); and the South Carolina Research Foundation (D.M.).
• Keywords: hippocampus; Life Sciences & Biomedicine; CA3; HIPPOCAMPAL CA3 NEURONS; Science & Technology; ION CHANNELS; MOSSY-FIBER SYNAPSES; zinc; SYNAPTIC-TRANSMISSION; AMPA RECEPTORS; GLUTAMATE-RECEPTOR; PHARMACOLOGICAL CHARACTERIZATION; mossy fiber; GRANULE CELLS; Neurosciences & Neurology; NMDA RECEPTORS; Neurosciences; kainate receptor; SUBUNIT; pH; glutamate receptor
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience

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 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.