Submitted on June 7, 2007
Accepted on January 19, 2008
Evidence that Xenon does not produce open channel blockade of the NMDA receptor
Henry Uwe Weigt1, Oliver Adolph2, Michael Georgieff2, Eva Maria Georgieff1, and Karl Josef Fohr1*
1 Clinic for Anesthesiology, University of Ulm, Ulm, Germany
2 Clinic for Anesthesiology, University of Ulm, Ulm, Germany; Ulm, Germany
* To whom correspondence should be addressed. E-mail: karl.foehr{at}uniklinik-ulm.de.
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 µM)-induced currents in the whole-cell recording mode. While Xe (3.5 mM) blocked the currents through the wild-type receptor NR1-1a/NR2A and NR1-1a/NR2B by about 40% and those through the mutant receptors NR1-1a/NR2A(A650C) or NR1-1a/NR2B(A651C) by about 30%, it was unable to block the currents through the methane thiosulfonate etyhlammonium (MTSEA)-modified mutant receptors. On the other hand, established open-channel blockers of the NMDA receptor such as MK-801 (1 µM) or Mg ions (Mg2+; 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.
