Unlike the water-soluble hormones, the lipophilic steroid and thyroid hormones do not travel dissolved in the aqueous portion of the plasma; rather, they are transported to their target cells attached to plasma carrier proteins. These hormones must then dissociate from their carrier proteins in the blood in order to pass through the lipid component of the plasma membrane and enter the target cell, within which their receptor proteins are located (fig 11.4).
■ Figure 11.4 The mechanism of action of a steroid hormone on the target cells. Some steroids bind to a cytoplasmic receptor, which then translocates to the nucleus. Other steroid hormones enter the nucleus and then bind to their receptor. In both cases, the steroid-receptor complex can then bind to a specific area of DNA and activate specific genes.
cell nucleus to activate genetic transcription (production of mRNA). The nuclear hormone receptors thus function as transcription factors that first must be activated by binding to their hormone ligands. The newly formed mRNA produced by the activated genes directs the synthesis of specific enzyme proteins that change the metabolism of the target cell in ways that are characteristic of the effects of that hormone on that target cell.
Each nuclear hormone receptor has two regions, or domains: a ligand (hormone)-binding domain and a DNA-binding domain (fig. 11.5). The receptor must be activated by binding to its hormone ligand before it can bind to a specific region of the DNA, which is called a hormone-response element. This is a short DNA span, composed of characteristic nucleotide bases, located adjacent to the gene that will be transcribed when the nuclear receptor binds to the hormone-response element.
The nuclear hormone receptors are said to constitute a su-perfamily composed of two major families: the steroid family and the thyroid hormone (or nonsteroid) family. In addition to the receptor for thyroid hormone, the latter family also includes the receptors for the active form of vitamin D and for retinoic acid (derived from vitamin A, or retinol). Vitamin D and retinoic acid, like the steroid and thyroid hormones, are lipophilic molecules that play important roles in the regulation of cell function and organ physiology.
Endocrine Glands 293
— Receptor protein for steroid hormone
— Receptor protein for steroid hormone
Genetic transcription mRNA
■ Figure 11.5 Receptors for steroid hormones. (a) Each nuclear hormone receptor protein has a ligand-binding domain, which binds to a hormone molecule, and a DNA-binding domain, which binds to the hormone-response element of DNA. (b) Binding to the hormone causes the receptor to dimerize on the half-sites of the hormone-response element. This stimulates genetic transcription (synthesis of RNA).
Modern molecular biology has ushered in a new era in endocrine research, where nuclear receptors can be identified and their genes cloned before their hormone ligands are known. In fact, scientists have currently identified the hormone ligand for only about half of the approximately seventy different nuclear receptors that are now known. The receptors for unknown hormone ligands are called orphan receptors. For example, the receptor known as the retinoid X receptor (abbreviated RXR) was an orphan until its ligand, 9-cis-retinoic acid (a vitamin A derivative) was discovered. The significance of this receptor will be described shortly.
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