Hormones: Diverse Structures for Diverse Functions:- Hormones Act through Specific High-Affinity Cellular Receptors
all hormones act through highly specific receptors in hormone-sensitive target cells, to which the hormones bind with high affinity. Each cell type has its own combination of hormone receptors, which define the range of its hormone responsiveness. Moreover, two cell types with the same type of receptor may have different intracellular targets of hormone action and thus may respond differently to the same hormone. The specificity of hormone action results from structural complementarity between the hormone and its receptor; this interaction is extremely selective, so structurally similar hormones can have different effects. The high affinity of the in teraction allows cells to respond to very low concentrations of hormone. In the design of drugs intended to intervene in hormonal regulation, we need to know the relative specificity and affinity of the drug and the natural hormone. Recall that hormone-receptor interactions can be quantified by Scatchard analysis, which, under favorable conditions, yields a quantitative measure of affinity (the dissociation constant for the complex) and the number of hormone-binding sites in a preparation of receptor.
The locus of the encounter between hormone and receptor may be extracellular, cytosolic, or nuclear, de pending on the hormone type. The intracellular consequences of hormone-receptor interaction are of at least six general types: (1) a change in membrane potential results from the opening or closing of a hormone-gatedion channel; (2) a receptor enzyme is activated by the extracellular hormone; (3) a second messenger (such as cAMP or inositol trisphosphate) generated inside the cell acts as an allosteric regulator of one or more en zymes; (4) a receptor with no intrinsic enzyme activity recruits a soluble protein kinase in the cytosol, which passes on the signal; (5) an adhesion receptor on the cell surface interacts with molecules in the extracellular matrix and conveys information to the cytoskeleton; or (6) a steroid or steroidlike molecule causes a change in the level of expression (transcription of DNA into mRNA) of one or more genes, mediated by a nuclear hormone receptor protein . Water-soluble peptide and amine hormones (insulin and epinephrine, for example) act extracellularly by binding to cell surface receptors that span the plasma membrane (Fig. 1). When the hormone binds to its extracellular domain, the receptor undergoes a conformational change analogous to that produced in an allosteric enzyme by binding of an effector molecule. The conformational change triggers the downstream effects of the hormone. A single hormone molecule, in forming a hormone receptor complex, activates a catalyst that produces many molecules of second messenger, so the receptor serves not only as a signal transducer but also as a signal amplifier. The signal may be further amplified by a signaling cascade, a series of steps in which a catalyst activates a catalyst, resulting in very large amplifications of the original signal. A cascade of this type occurs in the regulation of glycogen synthesis and breakdown by epinephrine . Epinephrine activates (through its receptor) adenylyl cyclase, which produces many molecules of cAMP for each molecule of receptor bound hormone. Cyclic AMP in turn activates cAMP dependent protein kinase, which activates phosphory lase kinase, which activates glycogen phosphorylase. The result is signal amplification: one epinephrine molecule causes the production of many thousands of molecules of glucose 1-phosphate from glycogen. Water-insoluble hormones (steroid, retinoid, and thy roid hormones) readily pass through the plasma mem brane of their target cells to reach their receptor proteins in the nucleus (Fig. 1). With this class of hormones, the hormone-receptor complex itself carries the message; it interacts with DNA to alter the expression of specific genes, changing the enzyme complement of the cell and thereby changing cellular metabolism . Hormones that act through plasma membrane receptors generally trigger very rapid physiological or bio chemical responses. Just seconds after the adrenal medulla secretes epinephrine into the bloodstream, skeletal muscle responds by accelerating the breakdown of glycogen. By contrast, the thyroid hormones and the sex (steroid) hormones promote maximal responses in their target tissues only after hours or even days. These differences in response time correspond to different modes of action. In general, the fast-acting hormones lead to a change in the activity of one or more preexisting enzymes in the cell, by allosteric mechanisms or covalent modification. The slower-acting hormones generally alter gene expression, resulting in the synthesis of more or less of the regulated protein(s).
FIGURE 1 Two general mechanisms of hormone action. The pep tide and amine hormones are faster acting than steroid and thyroid hormones.
