Etomidate and Propofol Binding Sites on GABAA Receptors: Overlapping but not Identical?

Abstract

γ‐Aminobutyric acid type A (GABAA) receptors, the major inhibitory neurotransmitter system in the mammalian brain, are an important target for general anesthetics including etomidate and propofol. Amino acid residues αM236 (TM1) and βM286 (TM3) were identified as directly contributing to a single anesthetic binding site with [3H]azietomidate photolabeling, and this binding site is probably located at the α‐β subunit interface in the transmembrane domain (Li et al., J. Neurosci. (2006) 26:11599). The validity and specificity of [3H]azietomidate photolabeling in GABAA receptors were also demonstrated in that paper, establishing a new approach to study binding sites for other anesthetics like propofol. Etomidate and propofol have similar anesthetic and pharmacologic actions, and they probably share a binding pocket in GABAA receptors according to reported electrophysiology data. Here, we studied the relationship of their sites in GABAA receptors using [3H]azietomidate photolabeling. We found that propofol produced a concentration‐dependent inhibition of [3H]azietomidate photolabeling. However, only half of the total labeling was inhibited at saturating propofol concentrations. This finding brings up an interesting idea: although propofol and etomidate may share a binding pocket in GABAA receptors, their exact binding sites may be partly different. Supported by NIH grant P01 GM 58448 to K.W. Miller.