Intracellular Localization of Corticosteroid Receptors in Brain: Potential Interactions with Signal Transduction Pathways

Abstract

Adrenal corticosteroids have diverse actions in the central nervous system (CNS). Glucocorticoids, the major adrenal corticosteroids, regulate the actions of several classical neurotransmitters and peptides, neuronal and glial proliferation and differentiation, neuronal survival, cognitive function, and behavior (1). Mineralocorticoids, e.g., aldosterone, regulate salt appetite and blood pressure (2, 3). As with other members of the steroid receptor superfamily, most actions of adrenal corticosteroids are mediated by intracellular receptors (4). Activated corticosteroid receptors bind to a glucocorticoid response element and interact with other transcription factors to regulate the expression of various genes (5–8). Two types of corticosteroid receptors have been described (7–9). A Type I receptor, which is identical to the classical mineralocorticoid receptor of the kidney, salivary glands, and colon, has a high affinity (K_D = 0.5 nM) and low capacity for endogenous glucocorticoids in the brain. It binds preferentially to corticosterone in the limbic brain, and presumably mediates the effects of circadian levels of circulating corticosterone on CNS function. In the cir-cumventricular regions and ventrolateral hypothalamus, the Type I receptor shows a preference for aldosterone, and may mediate the central effects of this mineralocorticoid on salt appetite and blood pressure. A lower affinity (K_D = 2.5–5 nM), high capacity Type II receptor, which is identical to the classical glucocorticoid receptor of the liver, has also been described in the CNS. It is thought to mediate the effects of stress levels of endogenous glucocorticoids and synthetic glucocorticoids, e.g., dexamethasone, on CNS function and central negative feedback regulation of plasma glucocorticoid levels.

Corticosteroid Receptor Immunoreactivity in the CNS

The availability of antibodies against Type I (10–12) and Type II (13–15) corticosteroid receptors has facilitated immunocytochemical studies on their distribution in various target tissues. Using MINREC anti-sera against peptides derived from the hinge and variable domains of the human renal Type I receptor cDNA (10, 11), and BUGR2 monoclonal antibody against rat liver Type II receptor (15), we have demonstrated the expression of both types of corticosteroid receptors in limbic, motor, sensory, and visceral neurons in the rat CNS (16–18). In most regions, the density of Type II-immunoreactive (ir) neurons is higher than Type I-ir neurons.