Interaction of 3β, 5α-tetrahydrodeoxycorticosterone in rat and guinea-pig neurons: a comparison of ca 2+- and gaba a-cl −-channel current modulation

Abstract

A comparison of the interaction of 3β, 5α-tetrahydrodeoxycorticosterone (TDOC) on voltage-gated Ca 2+- and the γ-aminobutyric receptor (GABA A) gated-Cl −-channels was examined in freshly dissociated guinea-pig (GP) and rat hippocampal CA1 neurons and rat hypothalamic ventromedial nucleus (VMN) neurons. The steady-state inhibition of the peak Ca 2+ channel current evoked by depolarized steps from −80 to −10 mV by TDOC increased in concentration-dependent manner with IC 50 values of 1 and 6 pM for rat and GP CA1 neurons, respectively and 3 nM for rat VMN neurons. TDOC rapidly and reversibly inhibited a fraction (up to 26%) of the total Ca 2+ channel current in all neurons. Intracellular dialysis with GDP-β-S (500 μM) significantly diminished the TDOC inhibition of the Ca 2+ channel current, suggesting a G-protein involvement. In neurons isolated from pertussis-toxin–treated animals by chronic intracerebroventricular (1000 ng/24/48 h) infusion, the TDOC inhibition was also significantly diminished, suggesting modulation by the Gα i and/or Gα 0 G-protein subunits. The peak GABA-gated inward Cl − current was enhanced in both species from 0.1 to 10 μM with the greatest increase (48% at 10 μM) seen in the VMN. There was no difference in the enhancement of the GABA current in the CA1 region of both species. The results show that in contrast to the 3α-series, the 3β-series weakly enhance the GABA-evoked Cl − current but potently inhibit the Ca 2+ channel current. In addition, these results also suggest a common mode of action and a lack of interspecies difference for this steroid.