MODULATION OF THE N-METHYL-D-ASPARTATE CHANNEL BY EXTRACELLULAR H+
MODULATION OF THE N-METHYL-D-ASPARTATE CHANNEL BY EXTRACELLULAR H+
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DOI：
10.1073/pnas.87.16.6445
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发表时间：
1990-08-01
影响因子：
11.1
通讯作者：
MORAD, M
中科院分区：
文献类型：
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作者：
TANG, CM;DICHTER, M;MORAD, M
在大鼠海马神经元中研究了外部 [H+] 对谷氨酸激动剂激活的全细胞和单通道电流的影响。在 6.6 至 8.0 的 pH 范围内，外部 [H+] 的变化对激动剂使君子氨酸和红藻氨酸激活的单价离子携带电流的幅度和动力学的影响可以忽略不计。另一方面，携带 N-甲基-D-天冬氨酸 (NMDA) 的二价离子激活电流受到细胞外 [H+] 的强烈调节。增加的外部 [H+] 抑制 NMDA 激活电流，而减少的外部 [H+] 增强 NMDA 激活电流。内部 [H+] 的变化对 NMDA 激活电流影响很小或没有影响。 NMDA 激活电流的调节主要是由于通道开口数量的变化造成的。单一电导率和单个开放停留时间均未受到显着影响。这些结果表明质子化位点位于通道的外部并且远离通道渗透路径。由于 H+、NMDA 和甘氨酸之间在激活电流方面的相互作用主要是非竞争性的，因此我们的结果表明 H+ 的调节作用与受体激动剂亲和力的变化无关。这些结果表明，[H+] 对 NMDA 受体通道的调节可能是一种内在的保护机制，通过该机制调节钙流入神经元，特别是在缺氧/缺血条件下。
The influence of external [H+] on whole-cell and single-channel currents activated by glutamate agonists was studied in rat hippocampal neurons. In the pH range between 6.6 and 8.0, changes in external [H+] had negligible influence on the amplitude and kinetics of the monovalent ion-carrying currents activated by the agonists quisqualate and kainate. The divalent ion-carrying N-methyl-D-aspartate (NMDA)-activated current, on the other hand, was strongly modulated by extra-cellular [H+]. Increased external [H+] suppressed, whereas decreased external [H+] enhanced, the NMDA-activated current. Changes in internal [H+] had little or no effect on the NMDA-activated current. Modulation of the NMDA-activated current resulted primarily from changes in the number of channels openings. Neither the unitary conductance nor the individual open dwell-times were significantly affected. These results suggest that the protonation site is on the external aspect of the channel and is far removed from the channel permeation pathway. Because interactions between H+, NMDA, and glycine in activating the current were predominantly noncompetitive, our results suggest that the modulatory effect of H+ was not associated with changes in receptor-agonist affinities. These results suggest that modulation of the NMDA-receptor channel by [H+] may be an intrinsic protective mechanism by which calcium influx into neurons is regulated, particularly in hypoxic/ischemic conditions.