Sites of alcohol and volatile anesthetic action on glycine receptors

The glycine receptor is a member of the cys-loop family of ligand-gated ion channels. The neurotransmitter glycine binds to the receptor to activate an intrinsic chloride channel and hyperpolarize neurons. Glycine receptors are targets for both alcohols and volatile anesthetics and show enhanced function in the presence of clinically relevant concentrations of ethanol, longer chain alcohols and volatile anesthetics. Site-directed mutagenesis techniques have identified residues in transmembrane segment one (I229), two (S267) and three (A288) that mediate the effects of alcohols and anesthetics, and drug binding is hypothesized to involve amino acids from all four transmembrane segments. Recent studies using crosslinking have shown association of regions of the receptor involved with channel gating and drug modulation to better define interfaces involved with signal transduction and drug binding. Mutagenesis and the substituted cysteine accessibility method have identified positions affecting drug action and water-accessible positions of the glycine receptor in all four transmembrane segments, as well as in the N-terminal region of the receptor. The goal of this review is to examine the effects of alcohols and volatile anesthetics on glycine receptors, with emphasis on the specific positions involved with drug action and potential candidates for further study. Comparisons between the current data known for drug binding and accessibility in the glycine receptor and other members of the ligand-gated ion channel family serve to elucidate the components of alcohol and volatile anesthetic drug binding cavities.