Differential modulation of the gamma-aminobutyric acid type C receptor by neuroactive steroids

gamma-Aminobutyric acid type C receptor channels (GABA(C)Rs) composed of rh o subunits are pharmacologically distinct from GABA(A) receptor channels (G ABA(A)Rs). This difference is illustrated by the insensitivity of homo-olig omeric rho(1) receptor channels to many known modulators of GABA(A)Rs, such as barbiturates and benzodiazepines. A number of endogenous metabolites of corticosterone and progesterone, known as neuroactive steroids, compose ye t another class of compounds that can modulate GABA(A)Rs. Here, several neu roactive steroids are shown to also modulate the rho(1) receptor channel. 5 alpha-Pregnane-3 alpha,21-diol-20-one (allotetrahydrodeoxycorticosterone), 5 alpha-pregnane-3 alpha-ol-11,20-dione (alphaxalone), and 5 alpha-pregnan e-3 alpha-ol-20-one (allopregnanolone) potentiated the GABA-evoked currents from rho(1) receptor channels and concomitantly altered the deactivation k inetics by prolonging the decay time. In contrast, 5 beta-pregnane-3 alpha- ol-20-one (pregnanolone), 5 beta-pregnane-3,20-dione (5 beta-dihydroprogest erone), and 5 beta-pregnane-3 alpha,21-diol-20-one (tetrahydrodeoxycorticos terone), all potentiators of GABA(A)Rs, inhibited the GABA-elicited current s of the rho(1) receptor channel. In comparison to GABA(A)Rs, the modulatio n of rho(1) receptor channels by these neuroactive compounds occurred with relatively high concentrations of the neuroactive steroids and was more pro minent in the presence of low concentrations of GABA, equivalent to fractio ns of the EC50 value of the rho(1) receptor channel. Structural comparison of these six neuroactive steroids reveals that the key parameter in determi ning the mode of modulation for the rho(1) receptor channel is the position of the hydrogen atom bound to the fifth carbon, imposing a trans- or cis-c onfiguration in the backbone structure. This is the first demonstration of isomeric compounds that can differentially modulate the activity of the rho (1) receptor channel.