Background: Previous studies have shown that specific amino acid residues in the putative second transmembrane segment (TM2) of the γ-aminobutyric acid receptor type A (GABAA) receptor play a critical role in the enhancement of GABAA receptor function by halothane, enflurane, and isoflurane. However, very little is known about the actions of sevoflurane and desflurane on recombinant GABAA receptors. The aim of this study was to examine the effects of sevoflurane and desflurane on potentiation of GABA-induced responses in the wild-type GABAA receptor and in receptors mutated in TM2 of the α1, α2, or β2 subunits. Methods: GABAA receptor α1 or α2, β2 or β3, and γ2s subunit cDNAs were expressed for pharmacologic study by transfection of human embryonic kidney 293 cells and assayed using the whole cell voltage clamp technique. Concentration-response curves and EC50 values for agonist were determined in the wild-type α1β2γ2s and α2β3γ2s receptors, and in receptors harboring mutations in TM2, such as α1(S270W)β2γ2s, α1β2(N265W)γ2s, and α2(S270I)β3γ2s. The actions of clinically relevant concentration of volatile anesthetics (isoflurane, sevoflurane, and desflurane) on GABA activated Cl- currents were compared in the wild-type and mutant GABAA receptors. Results: Both sevoflurane and desflurane potentiated submaximal GABA currents in the wild-type GABAA α1β2γ2s receptor and α2β3γ2s receptor. Substitution of Ser270 in TM2 of the α subunit by a larger amino acid, tryptophan (W) or isoleucine (I), as in α1(S270W)β2γ2s and α2(S270I)β3γ2s, completely abolished the potentiation of GABA-induced currents by these anesthetic agents. In contrast, mutation of Asn265 in TM2 of the β subunit to tryptophan (W) did not prevent potentiation of GABA-induced responses. The actions of sevoflurane and desflurane in the wild-type receptor and in mutated receptors were qualitatively and quantitatively similar to those observed for isoflurane. Conclusions: Positions Ser270 of the GABAA α1 and α2 subunits, but not Asn265 in the TM2 of the β2 subunit, are critical for regulation of the GABAA receptor by sevoflurane and desflurane, as well as isoflurane, consistent with the idea that these three volatile anesthetics share a common site of actions on the α subunit of the GABAA receptor.
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CITATION STYLE
Nishikawa, K., & Harrison, N. L. (2003). The actions of sevoflurane and desflurane on the γ-aminobutyric acid receptor type A: Effects of TM2 mutations in the α and β subunits. Anesthesiology, 99(3), 678–684. https://doi.org/10.1097/00000542-200309000-00024