11 beta-hydroxysteroid dehydrogenase bioactivity and messenger RNA expression in rat forebrain: localization in hypothalamus, hippocampus, and cortex.
In peripheral aldosterone target sites (e.g., kidney), 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) metabolizes corticosterone to inactive 11-dehydrocorticosterone and thus protects mineralocorticoid receptors from exposure to corticosterone in vivo. We have investigated whether 11 beta-OHSD could account for the site-specific differences in corticosteroid receptor sensitivity to corticosterone in rat brain. Enzyme activity, estimated as the percentage conversion of [3H]corticosterone to [3H]11-dehydrocorticosterone in the presence of NADP+ (200 microM), was: hippocampus, 55.8 +/- 2.7%; cortex, 52 +/- 3.1%; pituitary; 40 +/- 2%, hypothalamus, 26.1 +/- 1.2%; brain stem, 21.4 +/- 1.7%; and spinal cord, 12.3 +/- 1.8%. Northern blots, using [32P]dCTP-labeled probes from an 11 beta-OHSD cDNA clone derived from rat liver, showed expression of a single mRNA species in all brain areas, of identical size to 11 beta-OHSD mRNA in liver and kidney. Highest expression was found in hippocampus and cortex. In situ hybridization, using [35S]UTP-labeled cRNA probes, localized high mRNA expression to cerebral cortex (particularly parietal cortex, layer IV), hippocampus (highest in CA3), hypothalamic medial preoptic area and arcuate nuclei and anterior pituitary. In conclusion, there is localized 11 beta-OHSD mRNA expression and enzyme bioactivity in rat brain. The distribution of 11 beta-OHSD corresponds to areas of reduced glucocorticoid or mineralocorticoid receptor affinity for corticosterone. Therefore, 11 beta-OHSD may regulate the access of corticosterone to cerebral mineralocorticoid and/or glucocorticoid receptors and thus modulate corticosteroid effects on brain function.
Moisan
M P
MP
University of Edinburgh, Department of Medicine, Western General Hospital, UK.
Seckl
J R
JR
Edwards
C R
CR
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D001921:Brain / Q000201:enzymology; D002540:Cerebral Cortex / Q000201:enzymology*; D003345:Corticosterone / Q000031:analogs & derivatives / Q000378:metabolism; D015342:DNA Probes; D015870:Gene Expression; D006624:Hippocampus / Q000201:enzymology*; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000201:enzymology*; D007700:Kinetics; D008297:Male; D009474:Neurons / Q000201:enzymology; D009693:Nucleic Acid Hybridization; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D011919:Rats, Inbred Strains
D015342:DNA Probes; D012333:RNA, Messenger; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; C003552:11-dehydrocorticosterone; D003345:Corticosterone