pH-Dependent inhibition of kainate receptors by zinc
pH-Dependent inhibition of kainate receptors by zinc
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DOI：
10.1523/jneurosci.3567-07.2008
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发表时间：
2008-02-13
影响因子：
5.3
通讯作者：
Dingledine, Raymond J.
中科院分区：
文献类型：
--
作者：
Mott, David D.;Benveniste, Morris;Dingledine, Raymond J.
红藻氨酸受体有助于包括海马CA3区在内的皮质边缘回路中神经元的突触可塑性和节律振荡放电。我们使用锌螯合剂和缺乏锌转运蛋白的小鼠来表明，突触释放的锌抑制突触后红藻氨酸受体在苔藓纤维突触和限制频率促进红藻氨酸，但不是AMPA EPSC在θ模式刺激。外源性锌也抑制海藻酸盐对苔藓纤维轴突兴奋性的易化调节，但不抑制海藻酸盐对CA3轴突的抑制作用。重组红藻氨酸受体以亚基依赖性方式被生理相关浓度的锌抑制，其中含有KA1亚基的受体对亚微摩尔浓度的锌敏感。锌抑制不改变受体脱敏，也不明显的激动剂亲和力，只有弱的电压依赖性，这表明一个变构机制。因此，在锌的存在下，pH的下降通过减轻锌抑制而增强红藻氨酸受体。细胞外空间的酸化，如在重复活动期间发生的，因此可能有助于揭示红藻氨酸受体神经传递。我们的结论是，锌调制红藻氨酸受体在塑造CA3区红藻氨酸神经传递中发挥重要作用。
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.