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The GABA_A receptor is a target of many general anesthetics. The low affinity of general anesthetics has complicated the search for the location of anesthetic binding sites. Attention has focused on two pairs of residues near the extracellular ends of the M2 and M3 membrane-spanning segments, α₁Ser270/β₂Asn265 (15′M2) and α₁Ala291/β₂Met286 (M3). In the 4-Å resolution acetylcholine receptor structure, the aligned positions are separated by ∼10 Å. To determine whether these residues are part of a binding site for propofol, an intravenous anesthetic, we probed propofol's ability to protect cysteines substituted for these residues from modification by the sulfhydryl-specific reagentp-chloromercuribenzenesulfonate (pCMBS^-). pCMBS^- reacted with cysteines substituted at the four positions in the absence and presence of GABA. Because propofol binding induces conformational change in the GABA_Areceptor, we …