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Vol. 58, Issue 5, 1129-1136, November 2000
-Aminobutyric Acid Type A Receptor 
1-Subunit
M3 Membrane-Spanning Segment
Integrated Program in Cellular, Molecular and Biophysical Studies,
Columbia University College of Physicians and Surgeons, New York,
New York (D.B.W.), and the Department of Physiology and Biophysics,
Albert Einstein College of Medicine, Bronx, New York (M.H.A.)
Benzodiazepine binding to 
-aminobutyric acid type A
(GABAA) receptors allosterically modulates GABA
binding and increases the currents induced by submaximal GABA
concentrations. Benzodiazepines induce conformational changes in the
GABA-binding site in the extracellular domain, but it is uncertain
whether these conformational changes extend into the membrane-spanning
domain where the channel gate is located. Alone, benzodiazepines do not
open the channel. We used the substituted-cysteine-accessibility method
to investigate diazepam-induced conformational changes in the region of
the 
1-subunit M3 membrane-spanning segment. In the
absence of diazepam or GABA, pCMBS
did not react at a
measurable rate with cysteine-substitution mutants between
1Phe296 and 1Glu303. In the presence of
100 nM diazepam, pCMBS reacted with
1F296C, 1F298C, and 1L301C
but not with the other cysteine mutants between 1Phe296
and 1Glu303. These three mutants are a subset of the
five residues that we previously showed reacted with
pCMBS applied in the presence of GABA. The
pCMBS reaction rates with these three cysteine mutants
were similar in the presence of diazepam and GABA. Thus, diazepam,
which binds to the extracellular domain, induces a conformational
change in the membrane-spanning domain that is similar to a portion of
the change induced by GABA. Because diazepam does not open the channel, these results provide structural evidence that the diazepam-bound state
represents an intermediate conformation distinct from the open and
resting/closed states of the receptor. The diazepam-induced conformational change in the M3 segment vicinity may be related to the
mechanism of allosteric potentiation.
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