Volatile anesthetics are widely utilized drugs that can produce significant toxic effects, yet their molecular targets and mechanisms of action are poorly defined The overall aim of our research is to identify critical molecular sites in the nervous system where inhaled anesthetics act. This information is needed in order to design drugs with greater specificity for desirable actions and fewer toxic side-effects. The gamma-aminobutyric acid type A (GABAA) receptor is likely an important anesthetic target. Most GABAA receptors in mammalian brain are composed of alpha, beta, and gamma subunits. Molecular studies, largely obtained using expressed GABAA receptors lacking gamma subunits, have identified sites that appear critical for modulation by volatile anesthetics However, we have found that incorporation of gamma subunits into expressed GABAA receptors both reduces sensitivity to volatile anesthetics compared with gamma-less receptors, and essentially nullifies the impact of a mutation at the putative volatile anesthetic site on the alpha subunit (alpha S2701) Our working hypothesis is that the gamma subunit contains specific structural features that modulate volatile anesthetic actions on GABAA receptors. We propose to 1) ascertain the impact of the gamma subunit on GABAA receptor function in the presence and absence of volatile anesthetics, 2) locate portions of the gamma subunit that are critical for modulation of volatile anesthetic actions, and 3) determine how the subunit alters the effects of mutations at the putative alpha subunit anesthetic site.
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