Corticosteroid receptors regulate transcription in the nervous system

Intracellular binding sites selective for [³H]-CORT were first identified in various brain regions, in particular the hippocampus, of adrenalectomized rats. A similar autoradiographic pattern was obtained using [³H]-aldosterone as a ligand, suggesting that these receptors were mineralocorticoid receptors. The [³H]-dexamethasone-binding pattern shows selective differences in the pattern of binding compared to the CORT and aldosterone patterns, suggesting the existence of multiple cortico-steroid receptors. [³H]-CORT binding performed in the presence of unlabeled dexamethasone or aldosterone reveals that CORT binds to at least two receptor types in the brain.

Two high-affinity intracellular cortico-steroid receptors have been characterized and are distinguished on the basis of binding properties, amino acid sequence, neuroanatomical distribution and physiological function. The type I corticosteroid receptor, or mineralocorticoid receptor, is localized in various brain regions, including the septum and hippocampus [6]. The type I receptor binds CORT and aldosterone with high affinity, ~0.5 nM. The relative steroid binding affinity of the type I receptor for CORT is greater than or equal to that for aldosterone, which is greater than that for dexamethasone. The type I receptor is present in all subregions of the hippocampus, namely, in the CA1, CA2, CA3 and the granular cells of the dentate gyrus (Fig. 26-4).

Figure 26-4

Immunohistochemical localization of type I corticosteroid receptor (mineralocorticoid receptor) in the rat hippocampus. A: Mineralocorticoid immunoreactivity is concentrated in pyramidal cell fields of the cornu ammons (CA2). B: High-power photomicrograph (more...)

The type II corticosteroid receptor, also called the glucocorticoid receptor, is widely distributed in the brain and exhibits high-affinity binding to dexamethasone. The type II receptor binds with ten-fold lower affinity to cortico-sterone, 5 nM, as compared with the type I receptor. The relative binding affinities for steroid interaction with the glucocorticoid receptor are such that dexamethasone binding is greater than corticosterone binding, which is much greater than aldosterone binding. Glucocorticoids are present at high concentrations in all regions of the hippocampus, with the exception of the CA3 region, where concentrations are exceedingly low [7].

Mineralocorticoid and glucocoticoid receptors can coexist in the same neurons as evident from their demonstrated colocalization in the CA1 region of the hippocampus [8]. These CA1 neurons are exquisitely sensitive to the whole range of glucocorticoid concentrations. Because of their high affinity for corticosteroids, the type I receptors are approximately 80% occupied, suggesting that the number of type I receptors is likely to be the rate-limiting factor in mineralocorticoid receptor functioning. However, glucocorticoid receptor functions are most dependent on the extent of glucocorticoid receptor occupancy and are likely to be regulated by the concentration of the available steroid. The presence of multiple binding sites for cortico-steroids as well as their differing concentrations in different cell types form the molecular basis for their differential actions in the rat brain [9].

The mechanisms of corticosteroid receptor regulation of transcription have been elucidated

Both type I and type II corticosteroid receptors are members of a superfamily of ligand-activated transcription factors defined by protein sequence similarity. Included in this superfamily are various other steroid receptors, such as the estrogen receptor, as well as members of the retinoic acid receptor family and thyroid hormone receptors. The ligand-activated transcription factor superfamily is estimated to contain several hundred members. Mineralocorticoid and glucocorticoid receptors are each composed of four distinct protein regions, including an N-terminal region, a DNA-binding domain, a nuclear localization signal and a C-terminal hormone-binding region. The N-terminal region is associated with activation of transcription through an as yet unknown mechanism. The DNA-binding domain is a charged protein sequence, known as a zinc-finger. In this case, there are two fingers, each composed of the sequence Cys-X2-Cys-X13-Cys-X2-Cys. The C-terminal region binds glucocorticoids, which, when bound, initiate the conformational change of the receptor which facilitates its translocation.

In the cytoplasm, the mineralocorticoid and glucocorticoid receptors are associated with a large multiprotein complex which contains the heat shock proteins (HSP) HSP70 and HSP90 (Fig. 26-5). This complex maintains unbound corticosteroid receptors in a ligand-accessible but inactive protein conformation. Binding of ligand causes dissociation of receptors from the heat shock proteins, followed by translocation of the activated receptors to the nucleus. In the nucleus, ligand-bound corticosteroid receptors bind to a cis-acting element called glucocorticoid response element (GRE). The GRE is a 20-base palindromic sequence, TGGTACAAATGTTCT, and is also called an enhancer element because it generally functions to enhance transcription. The GRE can be positioned anywhere within the gene, not just in the promoter region. Modulation of corticosteroid-responsive genes occurs through interactions of the type I or II receptors, bound to the enhancer sequence, with the transcriptional complex.

Figure 26-5

Activation of glucocorticoid receptors. Glucocorticoids () diffuse across the plasma membrane and bind to the glucocorticoid receptor. Upon glucocorticoid receptor binding to the steroid, the receptor undergoes a conformational change which permits it (more...)

Ligand-bound corticosteroid receptors have been shown to interact to form heterodimers with other transcription factors, such as the jun protein. Such interactions are responsible for transactivation of the cis-regulatory sites known as AP-1 sites and for the glucocorticoid-mediated suppression of transcription, such as that seen in the pro-opiomelanocortin gene. A number of such specific protein interactions have been reported; these interactions and their locations relative to other transcription factors transform a ubiquitous steroid hormone signal into a tissue-specific, graded cellular response.