Hormone Receptors are of Central Importance
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p489-490
2025-11-04
84
Receptors Discriminate Precisely One of the major challenges faced in making the hormone-based communication system work is illustrated in Figure 1. Hormones are present at very low concentrations in the extracellular fluid, generally in the femto- to nanomolar range (10−15-10−9 mol/L). This concentration is much lower than that of the many structurally similar molecules (sterols, amino acids, peptides, and proteins) and other molecules that circulate at concentrations in the micro- to millimolar (10−6-10−3 mol/L) range. Target cells, therefore, must distinguish not only between different hormones present in small amounts but also between a given hormone and the 106- to 109-fold excess of other similar molecules. This high degree of discrimination is provided by cell-associated recognition molecules called receptors. Hormones initiate their biologic effects by binding to hormone-specific receptors, and since any effective control system also must provide a means of stopping a response, hormone-induced actions generally, but not always, terminate when the effector dissociates from the receptor.
Fig1. Specificity and selectivity of hormone receptors. Many different molecules circulate in the extracellular fluid (ECF), but only a few are recognized by hormone receptors. Receptors must select these molecules from among high concentrations of the other molecules. This simplified drawing shows that a cell may have no hormone receptors (Cell type 1), have one receptor (Cell types 2+5+6), have receptors for several hormones (Cell type 3), or have a receptor but no hormone in the vicinity (Cell type 4).
A target cell is defined by its ability to selectively bind a given hormone to its cognate receptor. Several biochemical features of this interaction are important in order for hormone-receptor interactions to be physiologically relevant: (1) binding should be specific, that is, displaceable by agonist or antagonist; (2) binding should be saturable; and (3) binding should occur within the concentration range of the expected biologic response.
Both Recognition & Coupling Domains Occur on Receptors
All receptors have at least two functional domains. A recognition domain binds the hormone ligand and a second region generates a signal that couples hormone recognition to some intracellular function. This coupling, or signal transduction, occurs in two general ways. Polypeptide and protein hormones and the catecholamines bind to receptors located in the plasma membrane and thereby generate a signal that regulates various intracellular functions, often by changing the activity of an enzyme. By contrast, the lipophilic steroid, retinoid, and thyroid hormones interact with intracellular receptors, and it is this ligand-receptor complex within the nucleus that directly provides the signal, generally to specific genes whose rate of transcription is thereby affected.
The domains responsible for hormone recognition and signal generation have been identified in the protein poly peptide and catecholamine hormone receptors. Like many other DNA-binding transcription factors, the steroid, thy roid, and retinoid hormone receptors have several functional domains: one site binds the hormone; another binds to specific DNA regions; a third is involved in the interaction with various coregulator proteins that result in the activation (or repression) of gene transcription; and a fourth region may specify binding to one or more other proteins that influence the intracellular trafficking of the receptor.
The dual functions of binding and coupling ultimately define a receptor, and it is the coupling of hormone binding to signal transduction, the so-called receptor-effector coupling—that provides the first step in amplification of the hormonal response. This dual purpose also distinguishes the target cell receptor from the plasma carrier proteins that bind hormone but do not generate a signal (see Table 1).
Table1. Comparison of Receptors With Transport Proteins
Receptors Are Proteins
Several classes of peptide hormone receptors have been defined. For example, the insulin receptor is a heterotetramer composed of two copies of two different protein subunits (α2 β2 ) linked by multiple disulfide bonds in which the extra cellular α subunit binds insulin and the membrane-spanning β subunit transduces the signal through the tyrosine protein kinase domain located in the cytoplasmic portion of this polypeptide. The receptors for insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) are generally similar in structure to the insulin receptor. The growth hormone (GH) and prolactin (PRL) receptors also span the plasma membrane of target cells but do not contain intrinsic protein kinase activity. Ligand binding to these receptors, however, results in the association and activation of a completely different protein kinase signaling pathway, the Jak-Stat pathway. Polypeptide hormone and catecholamine receptors, which transduce signals by altering the rate of production of cAMP through G-proteins, which are guanosine nucleotide-binding proteins that are characterized by the presence of seven membrane spanning domains. Protein kinase activation and the generation of cyclic AMP (cAMP, 3′5′-adenylic acid) is a downstream action of this class of receptor .
A comparison of several different steroid receptors with thyroid hormone receptors revealed a remarkable conservation of the amino acid sequence in certain regions, particularly in the DNA-binding domains. This observation led to the realization that receptors of the steroid and thyroid type are members of a large superfamily of nuclear receptors. Many related members of this family currently have no known ligand and thus are called orphan receptors. The nuclear receptor super family plays a critical role in the regulation of gene transcription by hormones, as described in Chapter 42.
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