BIOCHEMISTRY - L. Stryer - 1984

VOLUME 3

PART V. MOLECULAR PHYSIOLOGY

CHAPTER 35. HORMONE ACTION

Summary

Hormones are a chemically diverse group of compounds that integrate the activities of various Cells in Multicellular Organisms. cAMP plays a crucial role in mediating the action of many hormones (such as epinephrine and Glucagon), serving as a second messenger inside the target Cell. Hormones whose action is mediated by cAMP bind to specific receptors on the target cell's Plasma Membrane and activate adenylate cyclase. The latter is a membrane-bound enzyme that catalyzes the synthesis of cAMP from ATP. The coupling between Hormone Receptors and adenylate cyclase is mediated by a guanine nucleotide-binding protein (G protein). The activation of adenylate cyclase leads to an elevation of intracellular cAMP levels. The resulting cAMP, in turn, activates protein kinase, which phosphorylates one or more Proteins. For example, the phosphorylation of Glycogen synthase and phosphorylase kinase in Muscles and the Liver leads to the inhibition of glycogen synthesis and the activation of glycogen breakdown. This enzyme cascade significantly amplifies the initial hormonal stimulus. cAMP appeared early in evolution, initially as a starvation signal. Cholera toxin catalyzes the ADP-ribosylation of the G protein, resulting in the persistent activation of adenylate cyclase in intestinal epithelial cells. Consequently, cholera causes a massive efflux of Na+ and Water into the intestinal lumen.

Insulin activates anabolic processes (the synthesis of glycogen, Fatty acids, and proteins) while inhibiting Catabolism (specifically, The breakdown of glycogen and fats). Insulin exerts a profound effect on membrane transport processes; notably, it stimulates the uptake of glucose and Amino Acids into Muscle and adipose tissue cells. The biosynthetic precursors of the active hormone are preproinsulin and proinsulin, both of which consist of a single polypeptide chain. Preproinsulin contains a signal sequence that is cleaved within the lumen of rough Endoplasmic reticulum tubules. Subsequently, proinsulin is converted into insulin through the proteolytic Cleavage of the connecting peptide that links the A and B chains of the future active hormone. This conversion of prohormone to hormone takes place in the Golgi apparatus and in secretory granules. Insulin is recognized by specific receptors localized in The Plasma Membrane of target cells. Insulin deficiency, relative to the cellular demand for it, underlies Diabetes Mellitus. This condition, arising from various causes, is characterized by elevated glucose levels in the Blood and urine. In a small percentage of diabetes patients, abnormalities such as impaired conversion of proinsulin to insulin, altered molecular Structure of insulin, and defects in cell membrane insulin receptors have been discovered.

Endorphins and enkephalins are Brain Peptides that exert effects similar to opiates, particularly morphine. β-Endorphin is derived from pro-opiomelanocortin, a prohormone that also serves as the source for other biologically active peptides: corticotropin (ACTH), β-lipotropin, and melanocyte-stimulating hormones (α- and β-MSH). The junction regions between future hormones in pro-opiomelanocortin, as in proinsulin, contain pairs of basic amino acid residues. Low-molecular-weight proteins also function as growth hormones, as exemplified by nerve growth factor and epidermal growth factor. These proteins stimulate the division and differentiation of target cells, with their effects manifesting over hours and days. Similarly, the effects of Steroid Hormones (such as estradiol, progesterone, and cortisone) unfold over the course of several hours or days. The action of Steroids is directed primarily toward the Introduction/30.html">Regulation of Gene Expression. It has been shown that estradiol penetrates the target cell and binds to a specific receptor in the Cytosol. A second protein subunit attaches to the resulting complex, after which the entire complex enters The Nucleus, where it binds to specific DNA sequences. Prostaglandins, which are synthesized from polyunsaturated C₂₀ fatty acids, modulate the action of various hormones but are not hormones themselves. Aspirin inhibits prostaglandin synthesis through the Covalent Modification of the enzyme that catalyzes the incorporation of oxygen atoms during prostaglandin Biosynthesis.