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The family of nuclear receptors contains at least 48 genes and has been classically divided into two subfamilies based on structural homology. One subfamily consists of receptors for steroid hormones, including the glucocorticoids (see pp. 1018–1026), mineralocorticoids (see pp. 1026–1030), and androgens (see pp. 1097–1100), as well as estrogens and progesterone (see pp. 1116–1120). These receptors function primarily as homodimers (see Table 3-6). The other group includes receptors for retinoic acid, thyroid hormone (see pp. 1006–1010), and vitamin D (see pp. 1063–1067). These receptors appear to act as heterodimers (see Table 3-6). As we will see on page 956, other nuclear receptors recognize a wide range of xenobiotics and metabolites, and thereby modulate the expression of genes that encode transporters and enzymes involved in drug metabolism.
The intracellular localization of the different unoccupied receptors varies. The glucocorticoid (GR) and mineralocorticoid (MR) receptors are mainly cytoplasmic, the estrogen (ER) and progesterone (PR) receptors are primarily nuclear, and the thyroid hormone (TR) and retinoic acid (RAR) receptors are bound to DNA in the nucleus. Cytoplasmic receptors are frequently complexed to chaperone (or “heat shock”) proteins. Hormone binding induces a conformational change in these receptors that causes dissociation from the cytoplasmic chaperone and unmasks a nuclear transport signal that allows the hormone-receptor complex to translocate into the nucleus.
Nuclear receptors contain five to six functionally distinct domains (Fig. 3-14) that are differentially conserved among the various members of the family. The N-terminal A/B region differs most widely among receptors and contains the first of two transactivation domains. Transactivation is the process by which a ligand-induced conformational change of the receptor results in a change in conformation of the DNA and thus initiates transcription. The C region, the most highly conserved among receptor types, contains the DNA-binding domain and is also involved in dimerization (see Table 3-6). It is composed of two “zinc finger” structures (see p. 82). The D, or hinge, region contains the “nuclear localization signal” and may also contain transactivation sequences. The E domain is responsible for hormone binding. Like the C region, it is involved in dimerization via its “basic zipper” region (see p. 83). Finally, like the A/B region, the E region contains a transactivation domain. The small C-terminal F domain is present in only some nuclear receptors and is of unknown function.
FIGURE 3-14 Modular construction of intracellular (or nuclear) receptors. Members of this family exist in the cytoplasm or nucleus and include receptors for several ligands, including retinoic acid, vitamin D, thyroid hormones, and steroid hormones. These receptors have modular construction, with up to six elements. The percentages listed inside the A/B, C, and E domains refer to the degrees of amino-acid identity, referenced to the glucocorticoid receptor. Thus, the DNA-binding or C domain of the retinoic acid receptor is 45% identical to the corresponding domain on the glucocorticoid receptor.
Activated nuclear receptors bind to sequence elements in the regulatory region of responsive genes and either activate or repress DNA transcription
One of the remarkable features of nuclear receptors is that they bind very specifically to short DNA sequences—called hormone response elements—in the regulatory region of responsive genes. The various nuclear receptors display specific cell and tissue distributions. Thus, the battery of genes affected by a particular ligand depends on the complement of receptors in the cell, the ability of these receptors to form homodimers or heterodimers, and the affinity of these receptor-ligand complexes for a particular response element on the DNA.
In addition to affecting transcription by directly binding to specific regulatory elements, several nuclear receptors modulate gene expression by acting as transcriptional repressors (see p. 92). For example, the glucocorticoids, acting via their receptor, can attenuate components of the inflammatory response by suppressing the transcriptional activity of other transcription factors such as activator protein 1 (AP-1; see Table 4-1) and nuclear factor κB (NF-κB; see pp. 86–87).
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