R

Compelenl Effector Domain Available for Signal Transaction

FIGURE 1-5 Schematic model of a generic receptor for a hormone. The ligand-binding domains and the effector domains are indicated. Upon binding of the hormone (H), a conformational change occurs in the receptor, which converts a dormant effector domain into a competent effector domain (i.e., able to initiate signal transduction). The whole process of hormone binding and generation of a competent receptor followed by dissociation of the hormone is believed to operate in a cyclic fashion.

FIGURE 1-6 Cascade mechanism leading from the cell surface hormonal signal to the cellular metabolic response: glucagon and glycogenolysis. Glucagon combines with its cell membrane receptor (1), which stimulates the activity of adenylate cyclase, possibly mediated by a transducing element, on the cytoplasmic side of the membrane (2). The resulting increased level of cyclic AMP activates a protein kinase (3) by the mechanism shown in Fig. 1-37. The protein kinase subunits catalyze the phosphorylation of inactive phosphorylase kinase (5) and active glycogen synthetase (4) to produce the phosphorylated inactive form (6), which stimulates glycogenolysis (7) to form glucose 1-phosphate (G-l-P), which is further metabolized to glucose (8). Glucose is transported to the extracellular space and into general circulation (9). This represents a cascade system because each stimulated step after hormone binding is accomplished by an enzyme that can turn over multiple substrate molecules.

FIGURE 1-6 Cascade mechanism leading from the cell surface hormonal signal to the cellular metabolic response: glucagon and glycogenolysis. Glucagon combines with its cell membrane receptor (1), which stimulates the activity of adenylate cyclase, possibly mediated by a transducing element, on the cytoplasmic side of the membrane (2). The resulting increased level of cyclic AMP activates a protein kinase (3) by the mechanism shown in Fig. 1-37. The protein kinase subunits catalyze the phosphorylation of inactive phosphorylase kinase (5) and active glycogen synthetase (4) to produce the phosphorylated inactive form (6), which stimulates glycogenolysis (7) to form glucose 1-phosphate (G-l-P), which is further metabolized to glucose (8). Glucose is transported to the extracellular space and into general circulation (9). This represents a cascade system because each stimulated step after hormone binding is accomplished by an enzyme that can turn over multiple substrate molecules.

of the C-14 fatty acid myristate), or they may form oligomers, either covalently through the formation of disulfide bonds or noncovalently. Also, membrane receptors can be subjected to the process of endocy-tosis.

Since the hormone binds to the receptor's ligand domain noncovalently, after the signal transduction process is complete the hormone may reversibly dissociate, thus generating "free" or unliganded receptor available for a new round of signal transduction. In reality, after one round of signal transduction, inactiva-tion or degradation of both the hormone (via catabo-lism or metabolism in the case of steroid hormones) and the receptor (endocytosis or phosphorylation) may ensue. Thus, there is a continuing need for the renewal (biosynthesis and secretion) of the hormone by the endocrine gland and of the receptor by the population of target cells.

E. Hormones and Cascade Systems

Many endocrine systems incorporate some form of cascade mechanism into their operation. A cascade mechanism is an amplification system where an initial reaction results in the generation of multiple second reactions, each of which sets off multiple third reactions, etc. Two examples will be presented.

A classical biochemical cascade mechanism is generated by the action of a hormone, such as glucagon acting at the cell membrane to produce an increase in cyclic AMP (see Figure 1-6). The cascade may be visualized in terms of alterations of cellular metabolism, which generate the ultimate cellular response, stimulation of glycogenolysis to generate glucose for export to the extracellular space, and the general circulating system, as in the example given in Figure 1-6.

Another important endocrine cascade system involves the central nervous system (CNS), the hypothal-

amus, pituitary, and distal endocrine secreting glands, and final target issues (see Figure 1-7).

The cascade effect may be produced by a single event or signal in the external or internal environment. By either electrical or chemical transmission, a signal is sent to the limbic system and then to the hypothalamus, resulting in the secretion of a releasing hormone into the closed portal system connecting the hypothalamus and anterior pituitary. Releasing hormones may be secreted in nanogram amounts and have half-lives of about 3-7 min. In turn they signal the release of the appropriate anterior pituitary hormones, which may be secreted in microgram amounts with half-lives on the order of 20 min or longer. The anterior pituitary hormone elicits the secretion of the ultimate hormone, which may be secreted in many micrograms or milligram amounts and may be fairly stable. Thus, in terms of increasing stability of hormones as one proceeds down the cascade, together with increasing amounts of hor-

Environmental or internal signal

Electrical/chemical signal

Limbic system

Electrical/chemical signal

Limbic system

Ultimate hormone (mg)

Systemic effects

FIGURE 1-7 Hormonal cascade of signals from CNS to ultimate hormone. The target "gland" refers to the last hormone-producing tissue in the cascade that is stimulated by an appropriate anterior pituitary hormone. The dashed line indicates a negative feedback loop.

mones elaborated down the cascade, amplification of a single event at the outset could involve a factor of thousands to a millionfold. The ultimate hormone will operate on its receptors in many cell types, and these hormone-receptor complexes may stimulate the appearance of many phenotypes, augmenting the amplification built into the cascade system even further. Although not all signaling mechanisms involve this entire system, a good many do, as will be illustrated in later chapters.

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