Weigt Henry U, Fohr Karl J, Georgieff Michael, Georgieff Eva M, Senftleben Uwe, Adolph Oliver
Department of Anaesthesiology, SLK-Kliniken Heilbronn, Bad Friedrichshall, Germany.
Acta Neurobiol Exp (Wars). 2009;69(4):429-40. doi: 10.55782/ane-2009-1754.
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.
稀有气体氙（Xe）不仅抑制N-甲基-D-天冬氨酸受体（NMDARs），还抑制谷氨酸受体的另外两种亚型，即α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPARs）和海人藻酸受体。对AMPARs的初步研究表明，氙的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，我们分析了其他“非脱敏”AMPARs突变体，并将其与NMDARs的同源突变体进行比较。在电压钳制条件下，通过全细胞记录研究了转染编码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、海人藻酸、N-甲基-D-天冬氨酸）施加到细胞上。在与特定激动剂联合测试之前，将氙预孵育20秒。3.5 mM氙使3 mM谷氨酸激活5秒的AMPA野生型受体[GluR1(i)；GluR2(i,Q)]的峰值电流和平台电流分别降低了45%和55%。对于脱敏作用大大减弱或消除的突变型AMPARs，即GluR1(i)_L497Y、GluR1(i)_A636T(Lc)、GluR2(i,Q)_R649E和GluR2(i,Q)_A643T(Lc)，氙的降低作用明显较小，在4%至20%之间变化。相比之下，将野生型NR1-1a/NR2A受体与NR2A内具有点突变且显著减慢（NR2A_A651T(Lc)）或加速（NR2A_M823W）受体脱敏的受体进行比较时，未观察到氙的阻断能力有差异。因此，我们的数据表明，在AMPARs中，氙对通道的阻断与脱敏有关，而在NMDARs中未发现这种关系的证据。因此，氙似乎通过不同的分子机制对各种离子型谷氨酸受体发挥抑制作用。
