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Vol. 56, Issue 5, 1087-1093, November 1999
-Aminobutyric Acid Type A Receptor Determined by the Volume of a
Second Transmembrane Domain Residue
Department of Anesthesia and Critical Care, The University of
Chicago, Chicago, Illinois
-Aminobutyric acid type A (GABAA )receptors are targets
for allosteric modulation by general anesthetics. Mutation of Ser270 within the second transmembrane domain of the GABAA
receptor 
subunit can ablate the modulation of the receptor by the
anesthetic ether isoflurane. To investigate further the function of
this critical amino acid residue, we made multiple amino acid
substitutions at Ser270 and analyzed the concentration-dependent gating
by GABA and regulation by isoflurane in each mutant receptor. There is a strong negative correlation between the EC50 for GABA and
the molecular volume of the amino acid residue at position 270. Replacement of Ser by large residues such as His and Trp produced a
shift of the GABA concentration-response curve to the left, whereas replacement of Ser with Gly had the opposite effect. There also was a
strong negative association between the molecular volume of the amino
acid residue at 270 and the degree of enhancement of submaximal GABA
responses by isoflurane. These results indicate the significance of the
amino acid at position 270 in gating of the GABAA
receptor. In addition, the data on isoflurane are consistent with the
existence of a cavity of finite size in the region of 270 that may
be filled by the anesthetic molecule or by the side chain of a larger
residue at 270. The introduction of isoflurane, or of a large
residue, into this cavity may stabilize the open state of the
GABAA receptor relative to the closed state.
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