Xenon blocks AMPA and NMDA receptor channels by different mechanisms.
Xenon blocks AMPA and NMDA receptor channels by different mechanisms.
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氙通过不同的机制阻断 AMPA 和 NMDA 受体通道。
DOI：
10.55782/ane-2009-1754
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发表时间：
2009
影响因子：
1.4
通讯作者：
O. Adolph
中科院分区：
文献类型：
--
作者：
H. Weigt;K. J. Fohr;M. Georgieff;E. Georgieff;U. Senftleben;O. Adolph
稀有气体氙（Xe）不仅能抑制NMDA受体（NMDARs），还能抑制谷氨酸受体的另外两种亚型，即AMPA （AMPARs）和kainate受体。AMPARs的初步研究表明，Xe敏感性可能与受体脱敏有关。为了确定这一假设是否适用于所有谷氨酸受体，我们分析了额外的“非脱敏”AMPARs突变体，并将其与NMDARs的同源突变体进行了比较。在电压箝位条件下，用全细胞记录法研究了转染AMPA-或NMDA受体cDNA的Neuro2A或SH-SY5Y细胞的膜电流。通过快速灌注系统将激动剂（谷氨酸、盐酸盐、NMDA）应用于细胞。氙气预孵育20秒后，再与特定激动剂联合试验。Xe （3.5 mM）降低了AMPA野生型受体[GluR1(i)]的峰值和高原电流；GluR2(i，Q)]被3mm谷氨酸激活5 s，分别激活45%和55%。突变AMPARs表现出明显减少或消除的脱敏性，即GluR1(i)_L497Y, GluR1(i)_A636T(Lc), GluR2(i，Q)_R649E和GluR2(i，Q)_A643T(Lc)， Xe的减少明显较小，变化幅度在4%到20%之间。相比之下，野生型NR1-1a/NR2A受体与NR2A内存在点突变的受体相比，Xe的阻断能力没有差异，NR2A内的点突变显著减缓（NR2A_A651T(Lc)）或加速（NR2A_M823W）受体脱敏。因此，我们的数据表明，在AMPARs中，Xe的通道阻断与脱敏有关，而在NMDARs中，没有发现这种关系的证据。因此，Xe可能通过不同的分子机制对各种嗜离子性谷氨酸受体发挥抑制作用。
The noble gas xenon (Xe) inhibits not only NMDA receptors (NMDARs) but also the two other subtypes of glutamate receptor i.e. AMPA (AMPARs) and kainate receptors. Preliminary studies on AMPARs suggest that Xe sensitivity might be coupled to receptor desensitization. In order to find out if this hypothesis can be applied to all glutamate receptors, we analyzed additional 'non-desensitizing' AMPARs mutants and compared these with homologous mutants of NMDARs. Membrane currents of Neuro2A or SH-SY5Y cells transfected with cDNA encoding AMPA- or NMDA receptors were investigated by whole cell recordings under voltage clamp conditions. Agonists (glutamate, kainate, NMDA) were applied to the cells by means of a rapid perfusion system. Xenon was preincubated for 20 s before testing it in combination with the particular agonist. Xe (3.5 mM) reduced peak and plateau currents of AMPA wild-type receptors [GluR1(i); GluR2(i,Q)] activated for 5 s with 3 mM glutamate, by 45 and 55% respectively. With mutant AMPARs showing greatly diminished or abolished desensitization i.e. GluR1(i)_L497Y, GluR1(i)_A636T(Lc) GluR2(i,Q)_R649E and GluR2(i,Q)_A643T(Lc) the reduction by Xe was significantly smaller and varied by between 4 and 20%. In contrast, no difference in the blocking capacity of Xe was observed comparing wild-type NR1-1a/NR2A receptors with receptors having point mutations within NR2A that substantially slowed (NR2A_A651T(Lc)) or accelerated (NR2A_M823W) receptor desensitization. Thus, our data indicate that in AMPARs channel blockade by Xe is related to desensitization, whereas in NMDARs no evidence for such a relation was found. Thus, Xe seems to exert its inhibiting effect on various ionotropic glutamate receptors by different molecular mechanisms.
NMDAR 通道中亚基的交错。
DOI：
10.1016/s0006-3495(02)75331-9
发表时间：
2002
期刊：
Biophysical journal.
影响因子：
--
作者：
Sobolevsky,AlexanderI;Rooney,LeeAnn;Wollmuth,LonnieP
通讯作者：
Wollmuth,LonnieP
影响因子：
3.6
作者：
Johannes J. Krupp;B. Vissel;S. Heinemann;Gary L. Westbrook
通讯作者：
Johannes J. Krupp;B. Vissel;S. Heinemann;Gary L. Westbrook
影响因子：
14.9
作者：
Rubin, CM;Kimura, RH;Schmid, CW
通讯作者：
Schmid, CW