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NEUROPHARMACOLOGY

Neuroactive Steroids and Human Recombinant 1 GABA Receptors

Departments of Anesthesiology (W.L., X.J., J.H.S.) and Molecular Biology and Pharmacology (D.F.C.), Washington University School of Medicine, St. Louis, Missouri

The -aminobutyric acid type C (GABA_C) receptor is structurally related to the GABA_A receptors, yet quite distinct physiologically and pharmacologically. Neuroactive steroids are known to be potent and efficacious modulators of the GABA_A receptor, but they are less well characterized in their actions on the GABA_C receptor. We have examined the actions of neuroactive steroids and analogs on 1 (GABA_C) receptors expressed in Xenopus laevis oocytes, with two goals in mind. First, we tested a larger number of endogenous steroids, to determine whether particularly potent steroids could be found. Second, we examined the structure-activity relationship for steroid actions, and some mechanistic features, to determine the possible numbers of steroid binding sites and mechanisms of action. In total, 41 compounds were examined. Estradiols are inhibitors, essentially equipotent with picrotoxinin. No endogenous steroid tested was highly efficacious at potentiation. The results of the structure-activity studies and the effects of two mutations to the second transmembrane region of the 1 GABA_C receptor indicate that there are several mechanisms by which steroids can inhibit the receptor. Surprisingly, estradiol shares some features with picrotoxin. Inhibition by negatively charged compounds was not sensitive to membrane potential, and inhibition by all compounds tested was reduced at higher concentrations of GABA. The data indicate that the binding sites mediating potentiation and inhibition differ from each other and that there are several (three or more) mechanisms for producing inhibition.

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