Harpers

436 / CHAPTER 42◆❁❁✪✴ ❖❁◗❉ Figure 42–1. Specificity and selectivity of✧❙◆✪hormone receptors. Many different molecules✴❙ ECF circulate in the extracellular fluid (ECF), but✧❃❃content❍only a few are recognized by hormone receptors.Receptors must select these molecules❍◗✧❉❖✪❉❁❁from among high concentrations of the otherHormone molecules. This simplified drawing shows thatReceptor a cell may have no hormone receptors (1),have one receptor (2+5+6), have receptors for1 2 3 4 5 6 Cell types several hormones (3), or have a receptor butno hormone in the vicinity (4).plasma carrier proteins that bind hormone but do notgenerate a signal (see Table 42–6).Receptors Are ProteinsSeveral classes of peptide hormone receptors have beendefined. For example, the insulin receptor is a heterotetramer(α 2 β 2 ) linked by multiple disulfide bondsin which the extracellular α subunit binds insulin andthe membrane-spanning β subunit transduces the signalthrough the tyrosine protein kinase domain locatedin the cytoplasmic portion of this polypeptide. The receptorsfor insulin-like growth factor I (IGF-I) andepidermal growth factor (EGF) are generally similar instructure to the insulin receptor. The growth hormoneand prolactin receptors also span the plasma membraneof target cells but do not contain intrinsic proteinkinase activity. Ligand binding to these receptors,however, results in the association and activation of acompletely different protein kinase pathway, the Jak-Stat pathway. Polypeptide hormone and catecholaminereceptors, which transduce signals by alteringthe rate of production of cAMP through G-proteins,are characterized by the presence of seven domains thatspan the plasma membrane. Protein kinase activationand the generation of cyclic AMP, (cAMP, 3′5′-adenylic acid; see Figure 20–5) is a downstream actionof this class of receptor (see Chapter 43 for further details).A comparison of several different steroid receptorswith thyroid hormone receptors revealed a remarkableconservation of the amino acid sequence in certain regions,particularly in the DNA-binding domains. Thisled to the realization that receptors of the steroid orthyroid type are members of a large superfamily of nuclearreceptors. Many related members of this familyhave no known ligand at present and thus are called orphanreceptors. The nuclear receptor superfamily playsa critical role in the regulation of gene transcription byhormones, as described in Chapter 43.HORMONES CAN BE CLASSIFIEDIN SEVERAL WAYSHormones can be classified according to chemical composition,solubility properties, location of receptors,and the nature of the signal used to mediate hormonalaction within the cell. A classification based on the lasttwo properties is illustrated in Table 42–3, and generalfeatures of each group are illustrated in Table 42–4.The hormones in group I are lipophilic. After secretion,these hormones associate with plasma transport orcarrier proteins, a process that circumvents the problemof solubility while prolonging the plasma half-life of thehormone. The relative percentages of bound and freehormone are determined by the binding affinity andbinding capacity of the transport protein. The free hormone,which is the biologically active form, readily traversesthe lipophilic plasma membrane of all cells andencounters receptors in either the cytosol or nucleus oftarget cells. The ligand-receptor complex is assumed tobe the intracellular messenger in this group.The second major group consists of water-solublehormones that bind to the plasma membrane of the targetcell. Hormones that bind to the surfaces of cellscommunicate with intracellular metabolic processesthrough intermediary molecules called second messengers(the hormone itself is the first messenger), whichare generated as a consequence of the ligand-receptorinteraction. The second messenger concept arose froman observation that epinephrine binds to the plasmamembrane of certain cells and increases intracellularcAMP. This was followed by a series of experiments inwhich cAMP was found to mediate the effects of manyhormones. Hormones that clearly employ this mechanismare shown in group II.A of Table 42–3. To date,only one hormone, atrial natriuretic factor (ANF), usescGMP as its second messenger, but other hormoneswill probably be added to group II.B. Several hormones,many of which were previously thought to affectcAMP, appear to use ionic calcium (Ca 2+ ) or