title: Modulators of the glucocorticoid receptor also regulate mineralocorticoid receptor function.
abstract: Modulators are proposed to be novel ether aminophosphoglycerides that stabilize unoccupied and occupied glucocorticoid receptor steroid binding and inhibit glucocorticoid receptor complex activation. Two isoforms, modulator 1 and modulator 2, have been purified from rat liver cytosol [Bodine, P.V., & Litwack, G. (1990) J. Biol. Chem. 265, 9544-9554]. Since the mineralocorticoid receptor is relatively resistant to activation, modulator's effect on rat distal colon mineralocorticoid receptor function was examined. Warming of unoccupied receptor decreased residual specific [3H]aldosterone binding by 86 +/- 2%. Both modulator isoforms completely prevented this destabilization with Km's of 2 +/- 1 microM modulator 1 and 24 +/- 5 microM modulator 2. Warming of occupied mineralocorticoid receptors decreased [3H]aldosterone binding by 56 +/- 3%. Modulator only partially stabilized occupied receptor binding with Km's of 10 +/- 2 microM modulator 1 and 68 +/- 8 microM modulator 2. Modulator inhibited receptor activation with Km's of 3 +/- 1 microM modulator 1 and 33 +/- 10 microM modulator 2. Double-reciprocal analysis showed linear kinetics, and mixing modulator isoforms together had additive effects on unoccupied and occupied receptor steroid binding stabilization and activation inhibition. Colon cytosol contained a low molecular weight, heat-stable factor(s) which inhibited receptor activation and stabilized occupied receptor steroid binding. Molybdate completely stabilized unoccupied mineralocorticoid receptor steroid binding and inhibited activation with half-maximal effects at 3-4 mM but only stabilized occupied receptor binding by approximately 40%. These data indicate that (i) apparent physiologic concentrations of modulator stabilize mineralocorticoid receptor steroid binding and inhibit receptor activation, (ii) an aldosterone-responsive tissue contains a modulator-like activity, and (iii) molybdate mimics the effects of modulator.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
authors.forename: G
authors.initials: G
authors.lastname: Schulman
authors.forename: P V
authors.initials: PV
authors.lastname: Bodine
authors.forename: G
authors.initials: G
authors.lastname: Litwack
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003106:Colon / Q000737:chemistry; D003600:Cytosol / Q000737:chemistry; D004987:Ethers / Q000302:isolation & purification / Q000494:pharmacology; D005989:Glycerides / Q000302:isolation & purification / Q000494:pharmacology*; D006358:Hot Temperature; D008099:Liver / Q000737:chemistry*; D008297:Male; D008982:Molybdenum / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
chemical_list: D004987:Ethers; D005989:Glycerides; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid; C044659:molybdate; D000450:Aldosterone; D008982:Molybdenum