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The Journal of Neuroscience, January 5, 2005, 25(1):139-148; doi:10.1523/JNEUROSCI.3791-04.2005

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Cellular/Molecular
A Functional Interaction of Sodium and Calcium in the Regulation of NMDA Receptor Activity by Remote NMDA Receptors

Wen-Kuan Xin,^1,3 Chun L. Kwan,^1,3 Xiao-Han Zhao,^1,3 Jindong Xu,^1,3 Richard P. Ellen,² Christopher A. G. McCulloch,² and Xian-Min Yu^1,3,4

¹The Department of Oral Physiology and ²Canadian Institutes of Health Research Group in Matrix Dynamics, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada, ³Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada, and ⁴Department of Biomedical Science, College of Medicine, Florida State University, Tallahassee, Florida 32306-4300

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.

Key words: NMDA channel gating; intracellular sodium and calcium; single-channel activity; excitability; toxicity; synaptic plasticity

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Received March 16, 2004; revised November 12, 2004; accepted November 14, 2004.

This article has been cited by other articles:

				J. George, S. M. Dravid, A. Prakash, J. Xie, J. Peterson, S. V. Jabba, D. G. Baden, and T. F. Murray Sodium Channel Activation Augments NMDA Receptor Function and Promotes Neurite Outgrowth in Immature Cerebrocortical Neurons J. Neurosci., March 11, 2009; 29(10): 3288 - 3301. [Abstract] [Full Text] [PDF]

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