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

摘要: Gamma-aminobutyric acid type C receptor channels (GABA(C)Rs) composed of rho subunits are pharmacologically distinct from GABA(A) (GABA(A)Rs). This difference is illustrated by the insensitivity homo-oligomeric rho(1) to many known modulators GABA(A)Rs, such as barbiturates and benzodiazepines. A number endogenous metabolites corticosterone progesterone, neuroactive steroids, compose yet another class compounds that can modulate GABA(A)Rs. Here, several steroids shown also channel. 5alpha-Pregnane-3alpha,21-diol-20-one (allotetrahydrodeoxycorticosterone), 5alpha-pregnane-3alpha-ol-11, 20-dione (alphaxalone), 5alpha-pregnane-3alpha-ol-20-one (allopregnanolone) potentiated GABA-evoked currents concomitantly altered deactivation kinetics prolonging decay time. In contrast, 5beta-pregnane-3alpha-ol-20-one (pregnanolone), 5beta-pregnane-3, (5beta-dihydroprogesterone), 5beta-pregnane-3alpha, 21-diol-20-one (tetrahydrodeoxycorticosterone), all potentiators inhibited GABA-elicited comparison modulation these occurred with relatively high concentrations was more prominent in presence low GABA, equivalent fractions EC(50) value Structural six reveals key parameter determining mode for channel position hydrogen atom bound fifth carbon, imposing a trans- or cis-configuration backbone structure. first demonstration isomeric differentially activity