Xin Wen-Kuan, Kwan Chun L, Zhao Xiao-Han, Xu Jindong, Ellen Richard P, McCulloch Christopher A G, Yu Xian-Min
The Department of Oral Physiology, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada.
J Neurosci. 2005 Jan 5;25(1):139-48. doi: 10.1523/JNEUROSCI.3791-04.2005.
The NMDA receptor is an important subtype glutamate receptor that acts as a nonselective cation channel highly permeable to both calcium (Ca2+) and sodium (Na+). The activation of NMDA receptors produces prolonged increases of intracellular Ca2+ concentration ([Ca2+]i) and thereby triggers downstream signaling pathways involved in the regulation of many physiological and pathophysiological processes. Previous studies have focused on how Ca2+ or Na+ affects NMDA receptor activity in isolation. Specifically, [Ca2+]i increase may downregulate NMDA channels and thus is considered an important negative feedback mechanism controlling NMDA receptor activity, whereas an increase in intracellular Na+ concentration ([Na+]i) may upregulate NMDA channel activity. Thus so that the activity-dependent regulation of NMDA receptors and neuroplasticity may be further understood, a critical question that has to be answered is how an individual NMDA receptor may be regulated when both of these ionic species flow into neurons during the same time period via neighboring activated NMDA receptors. Here we report that the gating of a NMDA channel is regulated by the activation of remote NMDA receptors via a functional Na+-Ca2+ interaction and that during the activation of NMDA receptors Na+ influx potentiates Ca2+ influx on one hand and overcomes Ca2+-induced inhibition of NMDA channel gating on the other hand. Furthermore, we have identified that a critical increase (5 +/- 1 mM) in [Na+]i is required to mask the effects of Ca2+ on NMDA channel gating in cultured hippocampal neurons. Thus cross talk between NMDA receptors mediated by a functional Na+-Ca2+ interaction is a novel mechanism regulating NMDA receptor activity.
NMDA受体是一种重要的谷氨酸受体亚型，作为一种对钙（Ca2+）和钠（Na+）都具有高度通透性的非选择性阳离子通道。NMDA受体的激活会使细胞内Ca2+浓度（[Ca2+]i）持续升高，从而触发参与调控多种生理和病理生理过程的下游信号通路。以往的研究主要集中在Ca2+或Na+如何单独影响NMDA受体活性。具体而言，[Ca2+]i升高可能会下调NMDA通道，因此被认为是控制NMDA受体活性的一种重要负反馈机制，而细胞内Na+浓度（[Na+]i）升高可能会上调NMDA通道活性。为了进一步理解NMDA受体的活性依赖性调节和神经可塑性，一个必须回答的关键问题是，当这两种离子在同一时间段内通过相邻激活的NMDA受体流入神经元时，单个NMDA受体是如何被调节的。在此我们报告，NMDA通道的门控通过功能性Na+-Ca2+相互作用受远程NMDA受体激活的调节，并且在NMDA受体激活过程中，一方面Na+内流增强Ca2+内流，另一方面克服Ca2+诱导的NMDA通道门控抑制。此外，我们还确定，在培养的海马神经元中，[Na+]i需要临界升高（5±1 mM）才能掩盖Ca2+对NMDA通道门控的影响。因此，由功能性Na+-Ca2+相互作用介导的NMDA受体之间的相互作用是一种调节NMDA受体活性的新机制。
