Chapter 3 - Synthesis, metabolism, and actions of bioregulators

Abstract

Neurotransmitters, neurohormones, and hormones occur as peptides, proteins, modified amino acids (indoleamines, catecholamines, thyroid hormones), or lipids (steroids, eicosanoids). Peptides and protein neurohormones and hormones are synthesized as preprohormones and modified posttranslationally to prohormones and then cleaved again to the final product. These processes usually occur intracellularly. Additional posttranslational modifications may occur as well (e.g., addition of carbohydrates, dimer formation, amidation, acetylation). Peptides are secreted from endocrine epithelial cells by exocytosis and travel in the plasma unattached or bound to plasma proteins. Most steroids (including androgens, estrogens, progesterone, corticosteroids, and 1,25-DHC) and thyroid hormones, as well as many amines, are transported primarily bound to specific plasma proteins in equilibrium with a small quantity of free hormones. Peptides, proteins, indoleamines, catecholamines, thyroid hormones, and many other bioregulators are formed from one or more amino acids. The amino acid arginine is also the substrate for synthesis of the gaseous bioregulator nitric oxide. Steroid hormones are all derived from cholesterol, and the eicosanoids (prostaglandins, thromboxanes, leukotrienes) have a common precursor, arachidonic acid. Peptide, protein, and amine bioregulators bind to receptors located on the cell surface and typically produce their actions through production of second messengers. Some of these hormones work through mechanisms that employ a variety of G-proteins that influence levels of second messengers such as cAMP, IP3, and diacylglycerol, which in turn may affect the activity of specific protein kinases or permeability of the cell membrane. Other receptor complexes may exhibit protein kinase activities themselves and produce their effects through phosphorylation of specific proteins or by activation of phosphorylation cascades. Initial effects of these bioregulators usually alter membrane transport in (uptake) or out (secretion) of the cell or activate intracellular enzyme systems. Many of these membrane ligands also produce a delayed effect on protein synthesis through activation of cytosolic transcription factors. Cell surface receptors may cause an influx of Ca2+, which also functions as a second messenger. Steroids and thyroid hormones enter the cytoplasm where they may bind nuclear receptors, although they are sometimes located in the cytosol. Occupied receptors for these hormones typically form homo- or heterodimers and act as ligand-activated transcription factors, binding to hormone-response elements and affecting nuclear messenger RNA production (genomic actions) and subsequent protein synthesis. In a few cases, certain steroids may be ligands for receptors located in the cell membrane. Some steroids and T4 may be modified by intracellular enzymes prior to binding to receptors. Bioregulators are metabolized in a variety of ways to inactivate them so that activated cells can recover. Metabolism may involve inactivation by enzymes associated with the cell surface or by intracellular enzymes in the target cells or in nearby cells. The liver also is an important site for inactivation of hormones. Reuptake of amines by presynaptic neurons or adjacent cells is another method for inactivating the target cell. Steroids and thyroid hormones are often metabolized by addition of special components (e.g., sulfate, glucuronides) that increase their solubility in water and accelerate their excretion via the urine. Sensitivity of target cells also can be influenced by increases (upregulation) or decreases (downregulation) in receptor number.