Aldosterone modulates glucocorticoid receptor binding in hippocampal cell cultures via the mineralocorticoid receptor.
The regulation of corticosteroid receptor expression in the rat brain by adrenal steroids remains controversial. The results of in vivo studies [Brinton and McEwen, 1988; Luttge et al., 1989] suggest that activation of type I receptors can modulate both mineralocorticoid (MR; type I) and glucocorticoid (GR; type II) receptor binding in selected brain regions. The present study utilized primary hippocampal cell cultures from rats sacrificed at E19-20 days of gestation to examine the effects of RU 28362, corticosterone (CORT) and aldosterone (ALDO) on GR binding ([3H]dexamethasone +/- RU 28362). Four days of exposure to 10 nM RU 28362, a highly selective GR agonist, resulted in a robust (approximately 70%) decrease in GR binding. Similar exposure to 10 nM of either CORT or ALDO also produced a significant (50-55%) decrease in GR binding capacity. Scatchard analyses confirmed that the diminished GR binding capacity in response to ALDO was due to a decrease in total number of binding sites (Bmax for Control = 112 +/- 25 fmol/mg vs. ALDO = 48 +/- 12 fmol/mg) with no significant change in the affinity constant. The calculated EC50 from the ALDO concentration response curve was 3.5 nM. Competition studies demonstrated that such low nM concentrations of ALDO were unable to displace specific [3H]dexamethasone +/- RU 28362 binding. Spironolactone, a highly specific MR antagonist, inhibited the ALDO-induced down-regulation of GR binding. These findings support the hypothesis that MR activation can modulate GR binding in hippocampal cells.
O'Donnell
D
D
Douglas Hospital Research Center, Department of Psychiatry and Neurology, McGill University, Montreal, Que., Canada.
Meaney
M J
MJ
D000450:Aldosterone / Q000494:pharmacology*; D000732:Androstanols / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000493:pharmacokinetics; D015536:Down-Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000378:metabolism*; D013148:Spironolactone / Q000494:pharmacology
D000732:Androstanols; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone; C049154:11,17-dihydroxy-6-methyl-17-(1-propynyl)androsta-1,4,6-triene-3-one; D003907:Dexamethasone