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Summary: Benzodiazepines Induce a Conformational Change in the
Region of the -Aminobutyric Acid Type A Receptor
1-Subunit M3 Membrane-Spanning Segment
DANIEL B. WILLIAMS and MYLES H. AKABAS
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.)
Received April 27, 2000; accepted July 14, 2000 This paper is available online at http://www.molpharm.org
ABSTRACT
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 mem-
brane-spanning domain where the channel gate is located.
Alone, benzodiazepines do not open the channel. We used the
substituted-cysteine-accessibility method to investigate diaze-
pam-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
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