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Structural Evidence that Propofol Stabilizes Different GABAA Receptor States at Potentiating and Activating Concentrations
 

Summary: Structural Evidence that Propofol Stabilizes Different GABAA
Receptor States at Potentiating and Activating Concentrations
Daniel B. Williams,1,3 and Myles H. Akabas,1,2
Departments of 1Physiology and Biophysics and 2Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461,
and 3Integrated Program in Cellular, Molecular, and Biophysical Studies, Columbia University, New York, New York 10032
The GABAA receptor is a target of many general anesthetics,
such as propofol. General anesthetic binding sites are distinct
from the GABA binding sites. At low concentrations, the anes-
thetics potentiate the currents induced by submaximal GABA
concentrations. At higher concentrations the anesthetics di-
rectly activate GABAA receptors. In contrast, benzodiazepines,
such as diazepam, only potentiate currents induced by sub-
maximal GABA concentrations. Channel kinetic studies sug-
gest that these drugs stabilize different receptor states. We
previously showed that the accessibility of the anionic sulfhy-
dryl reagent p-chloromercuribenzenesulfonate (pCMBS ) ap-
plied extracellularly to cysteines substituted for residues in the
GABAA 1 subunit M3 membrane-spanning segment was
state-dependent. The subset of pCMBS -accessible, M3 seg-
ment cysteine mutants acts as a reporter for receptor confor-

  

Source: Akabas, Myles - Department of Physiology and Biophysics, Albert Einstein College of Medicine, Yeshiva University

 

Collections: Biology and Medicine