Neuroactive steroids and human recombinant ρ1 GABAC receptors

Wenjun Li, Xiaochun Jin, Douglas F. Covey, Joe Henry Steinbach

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

The γ-aminobutyric acid type C (GABAC) receptor is structurally related to the GABAA receptors, yet quite distinct physiologically and pharmacologically. Neuroactive steroids are known to be potent and efficacious modulators of the GABAA receptor, but they are less well characterized in their actions on the GABAC receptor. We have examined the actions of neuroactive steroids and analogs on ρ1 (GABAC) 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 ρ1 GABAC 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.

Original languageEnglish
Pages (from-to)236-247
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume323
Issue number1
DOIs
StatePublished - Oct 2007

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