Evidence that Xenon does not produce open channel blockade of the NMDA receptor.
Previous studies had not excluded the possibility that the mechanism by which Xenon (Xe) blocks N-methyl-D-aspartate (NMDA) receptors might be that of an open-channel blocker. We tested this possibility on mutant NMDA receptors carrying an alanine (A) to cysteine (C) mutation located within the SYTANLAAF-motif of the third transmembrane region (TM3). This mutation was shown to yield constitutively open ion channels after modification with a thiol-modifying reagent. We expressed such mutant channels in Neuro2A cells and recorded glutamate (50 microM)-induced currents in the whole cell recording mode. Although Xe (3.5 mM) blocked the currents through the wild-type receptor NR1-1a/NR2A and NR1-1a/NR2B by approximately 40% and those through the mutant receptors NR1-1a/NR2A(A650C) or NR1-1a/NR2B(A651C) by approximately 30%, it was unable to block the currents through the methane thiosulfonate etyhlammonium-modified mutant receptors. On the other hand, established open-channel blockers of the NMDA receptor such as MK-801 (1 microM) or Mg ions (Mg(2+); 1 mM) were able to block these permanently open channels. These results suggest that Xe does not act as a classical open-channel blocker at the NMDA receptor.
Weigt
Henry U
HU
Clinic for Anesthesiology, University of Ulm, Ulm, Germany.
Adolph
Oliver
O
Georgieff
Michael
M
Georgieff
Eva M
EM
Föhr
Karl J
KJ
D019943:Amino Acid Substitution; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists; D006801:Humans; D009154:Mutation / Q000502:physiology; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014978:Xenon / Q000494:pharmacology*
D018685:Anesthetics, Inhalation; D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D014978:Xenon; D016291:Dizocilpine Maleate