Mineralocorticoids (e.g., aldosterone, ALDO) and glucocorticoids (e.g., corticosterone, CORT) have traditionally been defined in terms of their peripheral actions on electrolyte and carbohydrate metabolism; however it is now known that they can exert a number of important behavioral and other actions in the brain. Most of these actions are mediated by genomic modulations of various neurochemicals following he interactions of ALDO and CORT with their intracellular Type I and Type II receptors. The relatively low affinity of Type II receptors for CORT, and ALDO, suggests an interaction with this receptor mainly during conditions of heightened secretion or exogenous steroid administration. Since Type I receptors display an equivalently high affinity for CORT and ALDO, both hormones have the capacity to compete for binding, and in doing so, may elicit different genomic actions. Before these steroid-receptor complexes can elicit this response, they must first undergo a temperature-dependent transformation to the nuclear/DNA binding form known as activation. One of the main goals of this grant is to compare the underlying biochemical causes and consequences of ALDO- vs. CORT-Type I receptor activation in mouse brain. For example, what are the changes in size, shape, density, subunit structure and in surface charge, hydrophobicity and DNA affinity of ALDO- vs. CORT-Type I receptor complexes resulting from and/or producing activation? Are there intermediate steps in this process, and if so, what are the kinetics and energy requirements for the final sequence of transformation? Does the rate and energy requirements of ALDO- vs CORT-Type I receptor association and dissociation changes as a consequence of activation? What role, if any, does RNA and RNase play in this process? What role, if any, do sulfhydryl groups on the Type I receptor play in the reversible binding of ALDO, CORT AND DNA? What are the pH, dose- and time-dependent actions of molybdate on these processes? Lastly, we will attempt to purify unoccupied, occupied-unactivated and occupied-activated Type I receptors from rat hippocampal brain samples. This work will involve the combined use of various biochemical differences between the receptors and a novel selective presaturation treatment prior to steroid affinity resin chromatography. Following this purification, we will be able to study a number of new questions including the possible roles or receptor phosphorylation/dephosphorylation. We could also try to generate monoclonal antibodies against these purified receptors for use in additional biochemical and immunohistochemical localization studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS024404-03
Application #
3408969
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1987-01-01
Project End
1992-12-31
Budget Start
1989-01-01
Budget End
1992-12-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Jaskoll, T; Luttge, W G; Sakai, D D et al. (1993) H-2 gene complex and corticosteroid responsiveness: evidence that the corticosteroid hormone signal transduction pathway in the adult mouse lung is not associated with haplotype-specific responses to corticosteroids. Steroids 58:400-6
Chou, Y C; Luttge, W G; Sumners, C (1991) Expression of mineralocorticoid type I and glucocorticoid type II receptors in astrocyte glia as a function of time in culture. Brain Res Dev Brain Res 61:55-61
Luttge, W G; Rupp, M E; Davda, M M (1989) Aldosterone-stimulated down-regulation of both type I and type II adrenocorticosteroid receptors in mouse brain is mediated via type I receptors. Endocrinology 125:817-24
Rachamin, G; Luttge, W G; Hunter, B E et al. (1989) Neither chronic exposure to ethanol nor aging affects type I or type II corticosteroid receptors in rat hippocampus. Exp Neurol 106:164-71
Luttge, W G; Kang, C G; Rupp, M E et al. (1989) Treatment of mouse brain cytosol with dextran-coated charcoal and high salt does not reveal a new glucocorticoid binder. Brain Res 493:190-3
Luttge, W G; Rupp, M E (1989) Differential up- and down-regulation of type I and type II receptors for adrenocorticosteroid hormones in mouse brain. Steroids 53:59-76
Rarey, K E; Luttge, W G (1989) Presence of type I and type II/IB receptors for adrenocorticosteroid hormones in the inner ear. Hear Res 41:217-21
Luttge, W G; Davda, M M; Rupp, M E et al. (1989) High affinity binding and regulatory actions of dexamethasone-type I receptor complexes in mouse brain. Endocrinology 125:1194-203
Luttge, W G; Rupp, M E; Emadian, S M (1989) Initial characterizations of nontransformed and transformed [3H ]aldosterone-type I receptor complexes in brain cytosol. Endocrinology 124:1813-21
Emadian, S M; Luttge, W G (1988) Effects of polyhydric and monohydric compounds on the stability of type I receptors for adrenal steroids in brain cytosol. J Neurochem 50:1456-60

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