Introduction to Molecular Biology: From Cells to Atoms - Anthony Rees, Michael Sternberg 2002

Cells and Molecules at Work
Action of Certain Vertebrate Hormones

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Fig. 41.1.

Hormones are substances produced by specialized Tissues in higher organisms that act as highly specific "chemical signals." The structures of hormones vary widely: Insulin, a hormone secreted by the Pancreas, is a protein (molecular weight 6,000), whereas the vasoactive amine (i.e., affecting Blood pressure) adrenaline, produced by The adrenal medulla, is a small aromatic molecule (molecular weight 172). The function of hormones is to transmit information from "sensor Cells" that are in direct contact with the external environment. Hormones diffuse easily throughout the Organism, and therefore, once released by their producing tissue, all tissues and Organs capable of responding to them do so almost simultaneously. Thanks to this general, coordinated response, all PARTS OF THE organism are brought into a state most suited to environmental conditions.

The same hormone can trigger metabolic changes in Different types of cells. For example, a rise in human blood glucose levels after a meal serves as a signal for the pancreas to secrete insulin, which stimulates A wide variety of target tissues (Liver, adipose tissue, Muscles) capable of utilizing glucose and thereby lowering its blood concentration. Glucose can then be used by tissues in energy-producing metabolic processes or stored as Glycogen for future use. When blood glucose drops back to normal, insulin secretion ceases, and target tissues return to their unstimulated state. Hormones are generally mobilized only when the metabolic status of the organism needs to be altered. All hormones can be divided into two large groups depending on where the primary response to them occurs: at The Cell surface, resulting from their interaction with Plasma Membrane-linked receptors, or intracellularly, through action on soluble receptors in the Cytoplasm or Nucleus.

Membrane Receptors are plasma Membrane Proteins (often glycosylated) capable of binding hormones. Receptors are specific, and their activation requires a precise steric match between them and the molecules acting upon them; each hormone has its own dedicated receptors. To be capable of responding to the diverse environmental signals transmitted by hormones, cells must bear an appropriate Complement of receptors on their surface. For example, a typical target cell such as a hepatocyte (liver cell) possesses receptors for insulin, Glucagon (also a polypeptide hormone), adrenaline, and many Other Hormones. When a hormone approaches a target cell, it binds to its specific receptors, triggering a cascade of events that lead to the required metabolic changes. The detailed mechanism by which hormone binding initiates subsequent events is not yet fully understood. For certain hormones, however, so-called effectors have already been identified.

Effectors are molecules that are activated by the hormone-receptor complex but do not respond to the free, unbound receptor. According to the so-called " mobile receptor hypothesis," the activation mechanism involves the diffusion of participating molecules within the membrane and their subsequent "docking." The most thoroughly studied effector is adenylate cyclase, which catalyzes The conversion of ATP to 3',5'-AMP (cyclic AMP, or cAMP). This enzyme can be activated by many receptors, implying that: 1) cAMP is capable of regulating various metabolic processes; and 2) different receptors may share a similar Structure—at least in those parts of their molecules that interact with the effector. In the example shown in Fig. 41.1, the receptor and effector do not interact directly with one another. The intermediate process through which hormone binding induces effector activation is termed Transduction, and the molecule mediating it is called a transducer.

A transducer is any molecule that responds to The formation of the hormone-receptor complex but is incapable of causing metabolic changes by itself through any means other than activating the effector.

A typical Mechanism of hormone Action (such as for adrenaline or the polypeptide glucagon) is illustrated in the upper part of Fig. 41.1. Upon binding to the receptor, the hormone enables it to associate with a transducer—the so-called G-protein—which in turn undergoes a conformational change upon receptor attachment, leading to the formation of a GTP-binding site. The G-protein–GTP complex then binds to the enzyme adenylate cyclase, resulting in Enzyme Activation and cAMP generation. Even in the absence of a hormone—meaning that G-protein molecules are predominantly in their inactive conformation (not complexed with GTP)—the effector enzyme still exhibits a baseline level of activity. This explains why hormones stimulate ongoing metabolic processes rather than "switching on" completely dormant ones. The advantage of using an enzyme as an effector is that such an effector ensures The production of a very large number of cAMP molecules, thereby amplifying the initial "hormonal signal." Molecules that function in this manner like cAMP are termed secondary messengers.

A secondary messenger is a molecule (such as cAMP, cGMP) or an ion (such as Ca²⁺) whose concentration within the cell increases under METABOLISM/18.html">The Influence of a hormone.

Cyclic AMP is capable of activating a variety of intracellular Enzymes, such as protein kinase. This enzyme consists of two subunits: one—the K subunit—possesses kinase activity (it attaches a РО²~₄ group to a substrate protein), while the other—the R subunit—plays a regulatory role. cAMP binding induces the dissociation of the R subunit from the K subunit, thereby activating the latter. The active K subunit then phosphorylates Other Enzymes, converting them from an inactive to an active form and thus initiating a cascade of metabolic reactions. The resulting effects can manifest rapidly (Changes in membrane permeability) or slowly (activation of protein and DNA Synthesis). Regulation via desensitization can occur when the number of receptors on a target cell drops below the level required to activate effectors. This state arises naturally as a phase of the normal response. When a cell receives a hormonal stimulus, hormone-receptor complexes aggregate in the membrane, internalize into the cell, and are subsequently degraded. Because this process of receptor removal from the membrane is rapid, whereas their replacement by newly synthesized or recycled receptors is relatively slow, the number of cell-surface receptors falls below the minimum required to sustain a hormonal response for a certain period. A cell in this state is said to be desensitized to the hormone.

Cytoplasmic receptors are typically soluble proteins capable of binding low-molecular-weight hormones, such as Steroids (Ch. 33). Steroids are highly specialized hormones that exert their effects within The Nucleus of specific target cells. Once secreted by the appropriate tissue (e.g., the adrenal cortex, which produces over 30 different steroids), steroids are distributed throughout the body via the bloodstream and, owing to their lipophilic nature, cross The Plasma Membrane into the cytoplasm of the target cell. Inside the cell, steroids bind to specific receptors. An example of a steroid hormone is progesterone, produced by the corpus luteum, which plays a crucial role in maintaining Pregnancy and regulating the Menstrual cycle. The action of progesterone is mediated by progesterone receptors.

The progesterone receptor is a dimeric molecule found in the cytoplasm of target cells, such as those in the mammary gland. Progesterone binding stabilizes the dimeric STRUCTURE OF THE receptor and induces a conformational change. The hormone-receptor complex is capable of crossing the nuclear membrane, although the exact mechanism of this process remains unclear. Once inside the nucleus, the complex binds to specific Chromatin sites and alters the Transcription rate of particular genes. Transcription stimulation leads to an increased yield of mRNA molecules and, consequently, elevated intracellular levels of the proteins they encode. Because progesterone alters transcription rates and increases mRNA concentration, the result of its action—like that of other hormones—is the enhancement of ongoing metabolic processes rather than the induction of novel ones. The scheme of progesterone action shown at the bottom of Fig. 41.1 represents an attempt to best reflect existing experimental data. The B-subunit of the progesterone-receptor complex binds to the DNA acceptor site, whereas its A-subunit attaches to the effector site, resulting in an increased rate of RNA polymerase activity and, consequently, a higher volume of mRNA synthesized from the corresponding genes.