The differential sensitivity of GABAA receptor subtypes to anesthetics led to the identification of residues in the trans-membrane region of α and β subunits that are critical for modulation of GABAA-R function by volatile anesthetics like isoflurane, and high dose (≥100 mM) ethanol (Mihic et al., 1997). These residues are located at TM2-15’ and TM3-4’ (helical numbering convention), and proposed to be part of a single intrasubunit water-filled binding pocket (Yamakura et al., 2001), the existence of which has also been predicted by homology modeling studies (Ernst et al., 2005). The TM2-15’ had been found independently to affect sensitivity to loreclezole and the structurally related intravenous anesthetic etomidate, in β subunits (Belelli et al., 1997).
