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Vol. 53, Issue 3, 530-538, March 1998
-Aminobutyric Acid Type A Receptor
Distinct from That for Isoflurane
Departments of
Anesthesia and Critical Care (C.E.R., Q.Y., S.E.F.,
N.L.H.) and
Pharmacological and Physiological Sciences (V.V.K.,
N.L.H.), and
Committee on Neurobiology (M.D.K.), University of Chicago,
Chicago, Illinois 60637
Both volatile and intravenous general anesthetics allosterically
enhance 
-aminobutyric acid (GABA)-evoked chloride currents at the
GABA type A (GABAA) receptor. Recent work has revealed that
two specific amino acid residues within transmembrane domain (TM)2 and
TM3 are necessary for positive modulation of GABAA and glycine receptors by the volatile anesthetic enflurane. We now report
that mutation of these residues within either GABAA 
2 (S270 or A291) or 
1 (S265 or M286) subunits resulted in receptors that retain normal or near-normal gating by GABA but are insensitive to
clinically relevant concentrations of another inhaled anesthetic, isoflurane. To determine whether receptor modulation by intravenous general anesthetics also was affected by these point mutations, we
examined the effects of propofol, etomidate, the barbiturate methohexital, and the steroid alphaxalone on wild-type and mutant GABAA receptors expressed in human embryonic kidney 293 cells. In most cases, these mutations had little or no effect on the actions of these intravenous anesthetics. However, a point mutation in
the 1 subunit (M286W) abolished potentiation of GABA by propofol but
did not alter direct activation of the receptor by high concentrations of propofol. These data indicate that the receptor structural requirements for positive modulation by volatile and intravenous general anesthetics may be quite distinct.
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