Intracellular Receptors

To reach intracellular receptors, agonists must get across the plasma membrane. The steroid hormones and vitamin D (see Chapters 40, 43, and 45-47) are derivatives of cholesterol and readily diffuse through the lipid bilayer of the plasma membrane because they are highly lipid soluble. Similarly, the thyroid hormones (see Chapter 39), which are a-amino acids, have large nonpolar constituents and penetrate cell membranes both by diffusion and to some extent by carrier-mediated transport. Retinoic acid (vitamin A) is also quite lipid soluble, as is the gas nitrous oxide (NO). With the exception of the soluble form of guanylyl cyclase, which is an intracellular receptor for NO (see Chapter 17), all of the known intracellular receptors belong to the nuclear receptor superfamily of transcription factors that includes receptors for the steroid hormones, thyroid hormone, vitamins D and A, and derivatives of arachidonic acid. Because no ligands have yet been identified for some members of this superfamily, they are known as "orphan" receptors.

Nuclear receptors enhance or repress expression of some genes in a manner that is both agonist specific and cell specific. They are comprised of a single long peptide chain that ranges in length from about 350 amino acids for the thyroid hormone receptor (see Chapter 39) to more than 1000 amino acids for the mineralocorticoid receptor (see Chapter 40). Functionally, they can be divided into three domains. The N-terminal region, which accounts for most of the variability in length, contains an activation function (AF1) that regulates the transcription-promoting activity of the receptor as a consequence of its interaction with other transcription factors. It may be phosphorylated at multiple sites, usually on serine or threonine residues but sometimes also on tyrosine residues. Phosphorylation may increase its ability to interact with other transcription factors. The middle portion is the region with the greatest similarity of amino acid sequence among family members and is the part that binds to DNA. The carboxyl-terminal portion contains the hormone binding domain and a second activation function. It also contains a leucine-rich sequence that provides a surface for dimer formation with another nuclear receptor molecule.

In the unactivated state, the steroid hormone receptor subfamily of nuclear receptors may be located in the cytoplasm or in the nucleus. In the absence of ligand, the steroid hormone receptor is associated with a large complex of chaperon proteins (also called heat shock proteins) and is folded in such a way that the DNA binding surface is masked by the associated proteins. Ligand binding produces a change in shape that activates the receptor and causes it to dissociate from the chaperon proteins. Upon activation, the receptor forms a dimer with another activated receptor molecule and binds to specific nucleotide sequences in DNA called hormone response elements. These elements might be located in the immediate vicinity of the promoters of responsive genes or at appreciable distances away. The receptors activate or repress transcription of specific genes either by interacting directly with the basal transcription complex at the promoter or indirectly through interactions with other proteins that serve as accessory factors and coregulators (Fig. 20). It is likely that there are many coregulatory proteins, and that the complement of such factors available in any particular cell contributes to the determination of which genes will be affected. It is noteworthy that the receptors for several different steroid hormones may bind to the same hormone response elements, although the complement of genes activated is quite hormone specific. This

Steroid Receptors With Response Element

FIGURE 20 General scheme of steroid hormone action. Steroid hormones penetrate the plasma membrane and bind to intracellular receptors found largely in the nucleus (except adrenal steroid receptors). Hormone binding activates the receptor, which forms complexes with other proteins and binds to specific acceptor sites (hormone response elements, HRE) on DNA to initiate transcription and formation of the proteins that express the hormonal response. The steroid hormone is then cleared from the cell.

FIGURE 20 General scheme of steroid hormone action. Steroid hormones penetrate the plasma membrane and bind to intracellular receptors found largely in the nucleus (except adrenal steroid receptors). Hormone binding activates the receptor, which forms complexes with other proteins and binds to specific acceptor sites (hormone response elements, HRE) on DNA to initiate transcription and formation of the proteins that express the hormonal response. The steroid hormone is then cleared from the cell.

apparent paradox may be resolved if we assume that the role of the hormone response element is simply to anchor the receptor to the DNA in responsive genes, but whether or not a particular gene is transcribed is also determined by the combination of interacting transcription activators that associate with the receptor and the basal transcription complex. The thyroid hormones and retinoic acid act by a slight variation of this scheme; unoccupied receptors are already bound to their response elements in the DNA and do not form complexes with chaperons. Unoccupied receptors are either inactive until the ligand is bound or act as repressors in the absence of hormone. These receptors may form heterodimers with each other and in some cases with orphan receptors. Further discussion of signal transduction by this superfamily is found in chapters that discuss the actions of the various hormones.

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