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Enviado por: fer14 12 agosto 2013
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Mechanism of Action of Hormones That Act on Nuclear Receptors
MITCHELL A. LAZAR
Hormones can be divided into two groups on the basis of where they function in a target cell. The first group includes hormones that do not enter cells; instead, they signal by means of second messengers generated by interactions with receptors at the cell surface. All polypeptide hormones (e.g., growth hormone), monoamines (e.g., serotonin), and prostaglandins (e.g., prostaglandin E2), use cell surface receptors (see Chapter 5). The second group, the focus of this chapter, includes hormones that can enter cells. These hormones bind to intracellular receptors that function in the nucleus of the target cell to regulate gene expression. Classic hormones that use intracellular receptors include thyroid and steroid hormones.
Hormones serve as a major form of communication between different organs and tissues. They allow specialized cells in complex organisms to respond in a coordinated manner to changes in the internal and external environments. Classic endocrine hormones are secreted by endocrine glands and are distributed throughout the body through the bloodstream. These hormones were discovered by purifying the biologically active substances from clearly definable glands.
Numerous other signaling molecules share with thyroid and steroid hormones the ability to function in the nucleus to convey intercellular and environmental signals. Not all of these molecules are produced in glandular tissues. Although some signaling molecules, such as classic endocrine hormones, arrive at target tissues through the bloodstream, others have paracrine functions (i.e., acting on adjacent cells) or autocrine functions (i.e., acting on the cell of origin).
In addition to the classic steroid and thyroid hormones, lipophilic signaling molecules that use nuclear receptors include derivatives of vitamins A and D, endogenous metabolites such as oxysterols and bile acids, and non-natural chemicals encountere
d in the environment (i.e., xenobiotics). These molecules are referred to as nuclear receptor ligands. The nuclear receptors for all of these signaling molecules are structurally related and are collectively referred to as the nuclear receptor superfamily.1-3 The study of these receptors is a rapidly evolving field, and more detailed information can be obtained by visiting
the Nuclear Receptor Signaling Atlas web site (http://www.nursa.org [accessed September 2010]).
52 Mechan ism of Action of Horm ones That hat Act on Nuclear Receptors
Precursors of vitamin D are synthesized and stored
in skin and activated by ultraviolet light; vitamin D can also be derived from dietary sources. Vitamin D is then converted in the liver to 25(OH)D (25-hydroxyvitamin D, calcidiol) and in the kidney to 1,25(OH)2 D3 (1,25-dihydroxyvitamin D3, calcitriol), the most potent natural ligand of the vitamin D receptor (VDR). The 1-hydroxylation of calcidiol is tightly regulated, and calcitriol acts as a ...
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