Differential blockade of gamma-aminobutyric acid type A receptors by the neuroactive steroid dehydroepiandrosterone sulfate in posterior and intermediate pituitary

Dehydroepiandrosterone sulfate (DHEAS) is a neuroactive steroid with antago nist action at gamma-aminobutyric acid type A (GABA(A)) receptors, Patch-cl amp techniques were used to investigate DHEAS actions at GABA(A) receptors of the rat pituitary gland at two distinct loci: posterior pituitary nerve terminals and intermediate pituitary endocrine cells, The GABA responses in these two regions were quite different, with posterior pituitary responses having smaller amplitudes and desensitizing more rapidly and more complete ly. DHEAS blockade of GABA(A) receptors in the two regions also was differe nt. In posterior pituitary, a site with an apparent dissociation constant o f 15 mu M accounted for most of the blockade, but a small fraction of block ade may be related to a site with a dissociation constant in the nanomolar range. In the intermediate robe, DHEAS sensitivities in the nanomolar and m icromolar ranges were clearly evident, in proportions that varied widely fr om cell to cell. Regardless of whether the GABA response of a cell was high ly sensitive or weakly sensitive to DHEAS, GABA alone evoked currents that were indistinguishable in terms of amplitude, desensitization kinetics, and GABA sensitivity. Thus, the structural elements responsible for DHEAS bloc kade have a highly selective impact on receptor function. GABA(A) receptors with nanomolar sensitivity to DHEAS have not been described previously. Th is suggests that DHEAS may have an important role in the modulation of neur opeptide secretion, and the diverse properties of GABA(A) receptors in the rat pituitary provide mechanisms for selective regulation of the different peptidergic systems of this gland.