Chunk #21 — Acute effects of ethanol on GABAA receptors — Direct effects on GABAA receptor subtypes — High dose effects of ethanol (>30 mM) on phasic inhibition
GABAA receptor subtypes associated with phasic inhibition are modulated by higher doses of ethanol. Using chimeric receptors, Mihic et al. (1997) identified a 45-amino-acid region spanning the second and third transmembrane domains required for the direct enhancement of glycine receptors by ethanol and volatile anesthetics. Moreover, the mutation of two residues (serine270 and alanine291) produces receptors insensitive to ethanol-induced potentiation. Interestingly, the volume of this putative ethanol ‘binding pocket’ dictates receptor sensitivity to ethanol (Wick et al. 1998; Ye et al. 1998). GABAA receptors possessing the serine270 mutation have altered receptor gating and are hypersensitive to GABA (Ueno et al. 2000). Moreover, knockin mice with the serine270 to histidine (S270H) mutation show marked abnormal behaviors, premature mortality, and prolonged miniature inhibitory post-synaptic currents (mIPSCs) (Homanics et al. 2005). Nonetheless, the mutation of leucine277 to alanine (L277A) in combination with S270H restored GABA sensitivity to near normal affinity while retaining ethanol and volatile anesthetic insensitivity in vitro (Borghese et al. 2006b). Importantly, gene knockin mice with both mutations show decreased sensitivity to ethanol potentiation (80 mM) and recover more quickly from
