Vol. 56, Issue 4, 752-759, October 1999

Differential Modulation of the -Aminobutyric Acid Type C Receptor by Neuroactive Steroids

Kendall D. W. Morris, Charles N. Moorefield, and Jahanshah Amin

Department of Pharmacology and Therapeutics, Department of Physiology and Biophysics, The Institute for Biomolecular Science (K.D.W.M., J.A.), and The Center for Molecular Design and Recognition (C.H.N.), University of South Florida, Tampa, Florida

-Aminobutyric acid type C receptor channels (GABA_CRs) composed of  subunits are pharmacologically distinct from GABA_A receptor channels (GABA_ARs). This difference is illustrated by the insensitivity of homo-oligomeric ₁ receptor channels to many known modulators of GABA_ARs, such as barbiturates and benzodiazepines. A number of endogenous metabolites of corticosterone and progesterone, known as neuroactive steroids, compose yet another class of compounds that can modulate GABA_ARs. Here, several neuroactive steroids are shown to also modulate the ₁ receptor channel. 5-Pregnane-3,21-diol-20-one (allotetrahydrodeoxycorticosterone), 5-pregnane-3-ol-11,20-dione (alphaxalone), and 5-pregnane-3-ol-20-one (allopregnanolone) potentiated the GABA-evoked currents from ₁ receptor channels and concomitantly altered the deactivation kinetics by prolonging the decay time. In contrast, 5-pregnane-3-ol-20-one (pregnanolone), 5-pregnane-3,20-dione (5-dihydroprogesterone), and 5-pregnane-3,21-diol-20-one (tetrahydrodeoxycorticosterone), all potentiators of GABA_ARs, inhibited the GABA-elicited currents of the ₁ receptor channel. In comparison to GABA_ARs, the modulation of ₁ receptor channels by these neuroactive compounds occurred with relatively high concentrations of the neuroactive steroids and was more prominent in the presence of low concentrations of GABA, equivalent to fractions of the EC₅₀ value of the ₁ receptor channel. Structural comparison of these six neuroactive steroids reveals that the key parameter in determining the mode of modulation for the ₁ receptor channel is the position of the hydrogen atom bound to the fifth carbon, imposing a trans- or cis-configuration in the backbone structure. This is the first demonstration of isomeric compounds that can differentially modulate the activity of the ₁ receptor channel.