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First published on January 28, 2009; DOI: 10.1124/mol.108.053629

0026-895X/09/7504-973-981$20.00
Mol Pharmacol 75:973-981, 2009

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Steroid Interaction with a Single Potentiating Site Is Sufficient to Modulate GABA-A Receptor FunctionFormula

John R. Bracamontes, and Joe Henry Steinbach

Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri

Neuroactive steroids are efficacious potentiators of GABA-A receptors. Recent work has identified a site in the {alpha}1 subunit of the GABA-A receptor, that is essential for potentiation by steroids. However, each receptor contains two copies of the {alpha}1 subunit. We generated concatemers of subunits so that the {alpha}1 subunits could be mutated separately and examined the consequences of mutations that remove potentiation by most neurosteroids ({alpha}1 Q241L, {alpha}1 Q241W). Concatemers were expressed in Xenopus laevis oocytes, and activation by GABA, potentiation by neurosteroids, and the agonist activity of piperidine-4-sulfonic acid (P4S) were determined. When the {alpha}1 Q241L mutation is present in {alpha}1 subunits the EC50 for activation by GABA is shifted to higher concentration and potentiation by neurosteroids is diminished. When the {alpha}1 Q241W mutation is expressed, the EC50 for GABA is shifted to lower concentration, the relative efficacy of P4S is increased, and potentiation by neurosteroids is diminished. Mutation of only one {alpha}1 subunit does not produce the full effect of mutating both sites. Overall, the data demonstrate that at a macroscopic level, the presence of a single wild-type steroid-binding site is sufficient to mediate responses to steroid, but both must be mutated to completely remove the effects of steroids. Differences between the two sites seem to be relatively subtle.

Received for publication November 21, 2008.

Accepted for publication January 28, 2009.

Address correspondence to: Joe Henry Steinbach, Department of Anesthesiology, Washington University School of Medicine, Campus Box 8054, 660 S. Euclid Ave, St. Louis, MO 63110. E-mail: jhs{at}morpheus.wustl.edu






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