PT  - JOURNAL ARTICLE
AU  - Kendall D. W. Morris
AU  - Charles N. Moorefield
AU  - Jahanshah Amin
TI  - Differential Modulation of the γ-Aminobutyric Acid Type C Receptor by Neuroactive Steroids
DP  - 1999 Oct 01
TA  - Molecular Pharmacology
PG  - 752--759
VI  - 56
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/56/4/752.short
4100  - http://molpharm.aspetjournals.org/content/56/4/752.full
SO  - Mol Pharmacol1999 Oct 01; 56
AB  - γ-Aminobutyric acid type C receptor channels (GABACRs) composed of ρ subunits are pharmacologically distinct from GABAA receptor channels (GABAARs). This difference is illustrated by the insensitivity of homo-oligomeric ρ1 receptor channels to many known modulators of GABAARs, 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 GABAARs. Here, several neuroactive steroids are shown to also modulate the ρ1receptor channel. 5α-Pregnane-3α,21-diol-20-one (allotetrahydrodeoxycorticosterone), 5α-pregnane-3α-ol-11,20-dione (alphaxalone), and 5α-pregnane-3α-ol-20-one (allopregnanolone) potentiated the GABA-evoked currents from ρ1 receptor channels and concomitantly altered the deactivation kinetics by prolonging the decay time. In contrast, 5β-pregnane-3α-ol-20-one (pregnanolone), 5β-pregnane-3,20-dione (5β-dihydroprogesterone), and 5β-pregnane-3α,21-diol-20-one (tetrahydrodeoxycorticosterone), all potentiators of GABAARs, inhibited the GABA-elicited currents of the ρ1 receptor channel. In comparison to GABAARs, the modulation of ρ1 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 ρ1 receptor channel. Structural comparison of these six neuroactive steroids reveals that the key parameter in determining the mode of modulation for the ρ1 receptor channel is the position of the hydrogen atom bound to the fifth carbon, imposing a trans- orcis-configuration in the backbone structure. This is the first demonstration of isomeric compounds that can differentially modulate the activity of the ρ1 receptor channel. The American Society for Pharmacology and Experimental Therapeutics