The influence of neuroactive steroid lipophilicity on GABAA receptor modulation: evidence for a low-affinity interaction.

ABSTRACT: Anesthetic steroids with actions at gamma-aminobutyric acid type A receptors (GABA(A)Rs) may access transmembrane domain binding site(s) directly from the plasma cell membrane. Accordingly, the effective concentration in lipid phase and the ability of the steroid to meet pharmacophore requirements for activity will both contribute to observed steady-state potency. Furthermore, onset and offset of receptor effects may be rate limited by lipid partitioning. Here we show that several GABA-active steroids, including naturally occurring neurosteroids, of different lipophilicity differ in kinetics and potency at GABA(A)Rs. The hydrophobicity ranking predicted relative potency of GABA(A)R potentiation and predicted current offset kinetics. Kinetic offset differences among steroids were largely el

SUBMITTER: Chisari M 

PROVIDER: S-EPMC2724350 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature