See also Hormones, generally See also Signal transduction
Introduction:
Hormones may be categorized as lipophilic (fat-soluble), which are nonpolar, or hydrophilic (water-soluble), which are polar. The lipophilic hormones include the steroid hormones and the thyroid hormones.
Hydrophilic hormones are freely soluble in blood, but cannot pass through the plasma membrane of target cells. Their receptors are transmembrane proteins that bind to the hormone outside the cell, and transmit the signal to the interio. In contrast, lipophilic hormones travel in the blood bound to soluble transport proteins. But when they reach a target cell, they can cross the plasma mebrane and bind to intracellular receptors.
Protein Hormones:
Prolactin (PRL): is released by the anterior pituitary and sitmulates the mammary glands to produce milk in mammals. It also has diverse effects on many other targets, icnluding reulgaiton of ion and water transport across epitheila and activation of parental behaviors.
Glycoprotein hormones:
Glycoprotein hormones are a group of evolutionary conserved hormones involved in the regulation of reproduction and metabolism. Structurally, the glycoprotein hormones are related heterodimers comprised of a common alpha subunit and a hormone specific beta subunit. This family of hormones includes the following members:
Follicle-stimulating hormone (FSH): is produced by the anterior pituitary and is required for the devleopment of ovarian folicles in feamles. In males, it is required for the development of sperm. FSH stimultes the conversion of testosterone into estrogen in females, and into dihydroxytestosterone in males. FSH adn LH below are collectively referred to as gonadotropins.
Growth Hormone (somatotropin): is released by the anterior pituitary and stimulates the growth of muscle, bond (indirectly) and other tissues, and is also essential for proper metabolic regulation.
Luteinizing hormone (LH): stimulates the production of estrogen and progesterone by the ovaries and is needed for ovulation in femal reproductive cycles. In males, it stimules the testes to produce testosterone, which is needed for sperm production and for the development of male secondary sexual characteristics. It is produced by the anterior pituitary.
Thyroid stimulating hormone (TSH or thyrotropin): TSH is a 28-30 kDa heterodimeric glycoprotein produced in the thyrtrophs of the anterior pituitary gland. TSH stimualtes the thyroid gland to produce the hormone thyroxin, which in turn regulates development and metabolism by acting on nuclear receptors. This hormone controls thyroid function by interacting with the G protein coupled TSH receptor which leads to the stimulation of pathways involving secondary messenger molecules, such as cyclic adenosine 3’5′-monophosphate (cAMP), and ultimately results in the modulation of thyroidal gene expression. Physiological roles of TSH include stimulation of differentiated thyroid functions, such as iodine uptake and the release of thyroid hormone from the gland, and promotion of thyroid growth.
Chorionic gonadotrophin (CG)
Amino Acid Derived Hormones:
Amino acid derivatives are hormones manufactured by enzymatic modificaiton of specific amino acids. They include hormones secreted by the adrenal medulla (the inner portion of the adrenal gland), thyroid and pineal glands. Those secreted by the adrenal medulla are derived form tyrosine. Known as catecholamines, they include epinephrine (adrenaline) or norepinephrine (noradrenaline). Other hormones derived from Trrosine are the thyroid hormones, created by the thyroid gland. The pineal gland secretes a different amine hormone, melatonin, derived form tryptophan.
Norepinephrine (noradrenaline): is an amino acid derived hormone (a catecholamine). Noreipnephrine is secreted into the blood by the adrenal glands, but it is also released as a neurotransmitter by sympathetic nerve endings. Norepinephrine acts as a hormone to coordinate the activity of the heart, liver, and blood vessels druing reponses to stress.
Epinephrine (adrenaline) (see below) and norepinephrine (noradrenaline) are both hormones and neurotransmitters involved in the “fight-or-flight” response, but they differ in their primary actions and effects on the body, with epinephrine primarily affecting the heart and lungs, while norepinephrine mainly focuses on blood vessels.
Peptide Hormones:
Adrenocorticotropic hormone (ACTH or corticotropin) stimulates the adrenal cortex to produce corticosteroid hormones, including cortisol (in humans) and corticosterone (in many other vertibrates). These hormones regulate glucose homeostasis and are important in teh response to stress.
Glucagon: is a hormone that mobilizes glucose as part of the body’s mechanism to control blood glucose. This involves breaking down stored glycogen into glucose and turning on the genes that encode the enymes necessary to synthesize glucose.
Glucagon is a pancreatic hormone of 29 amino acids that regualtes carbohydrate metabolism and licentin is an intestinal peptide of 69 amino acids that contains the sequence of glucagon flanked by peptide extensions at the amino and carboxy terinal. The glucagon gene encodes a precursor containing glucagon and two additional, structurally related, glucagon-like peptides separated by an intervening peptide. These peptides are encoded in separate exons. Preproglucagon mRnAs are identical, but different and highly specific peptides are liberated in pancreatic and intestinal extracts. (The diversifciation of preproglucagon gene expression occurs at the level of cell specific post translational processing. Mojsov “Preproglucagon gene expression in pancreas and intestine diversified at the level of post-translational processing” J. Biol. Chemistry, 1986)
The glucagon gene encodes a proglucagon that contains in its sequence glucagon and additional glucagon-like peptides (GLPs). These GLPs are liberated from proglucagon in both the pancreas and intestines. GLP-I exists in at least two forms: 37 amino acids GLP-I (1-37) and 31 amino acids (GLP-I (7-37). In the presence of 6.6 mM glucose, GLP-I (7-37) is a potent stimulator of insulin secretion whereas GLP-I (1-37) had not effect on insulin secretion in an isoalted perfused rat pancreas. The earlier demonstration of specific liberation of GLP-I (7-37) in the intestine and pancreas, and the magnitude of the insulinotropic effect as such low concentrations, sugggested that GLP-I (7-37) participates in the physiological regulation of insulin secretion. (Mojsov “Insulinotropin: Glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas” (October 28, 1986).
Analysis of the cDNAs and genes encoding preproglucagon, a biosynthetic precursor of glucagon, reveals the presence of two additional glucagon-like petpides, GLP-I and GLP-II, each flanked by pairs of basic amino acids characteristics of the sites that are cleaved during the postranslational processing of prohormones. (Drucker “Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line” Proc. Natl. Acad. Sci, USA, vol. 84, pp. 3434-3438, May 1987).
Insulin: lowers blood glucose level, stimulates glycogen, fat, and protein synthesis.
Insulin is a hormone that helps regulate the body’s metabolism and blood sugar levels. It is produced by the pancrease and released into the blood when blood sugar levels rise, such as after eating. Insulin assists glucose to enter the cells, where it is used for energy. While glucagon keeps blood glucose from dropping too low, insulin is produced to keep blood glucose from rising too high.
Insulin is a peptide hormone secreted in the body by beta cells of islets of Langerhans of the pancreas and regulates blood glucose levels. Medical treatment with insulin is indicated when there is inadequate production of increased insulin demands in the body. In Type 1 or juvenile diabetes mellitus, pancreatic beta cells are destroyed by the body’s immune system or trauma or injury to the pancreas, leading to decreased or absent insulin production. Patients with type 1 diabetes always require insulin. Type 2 diabetes mellitus is the most common type of diabetes and usually occurs after 45 years. In type 2 diabetes, cells are resistant to the action of insulin. As a result, glucose starts building up in the blood. Treatment with insulin is necessary for the later stages of type 2 diabetes.
Insulin acts by directly binding to its receptors on the plasma membranes of the cells. These receptors are present on all the cells, but their density depends on the type of cells, with the maximum density on hepatic cells and adipocytes.
The role of insulin is thus to lower blood glucose, acting by binding to an RTK. The insulin receptor is a heterotetrameric glycoprotein consisting of two subunits, the alpha and beta subunits. The extracellular alpha subnunits have insulin binding sites. The beta subunits, which are transmembranous, have tyrosine kinase activity. When insulin binds to the alpha subunits, it activates the tyrosine kinase activity in the beta subunit, which causes the translocation of glucose transporters from the cytoplasm to the cell’s surface. Another protein called the insulin response protein binds to the phosphorylated receptor and is itself phosphrylated. The insulin response protein passes the signal on by binding to additional proteins that lead to the activation of the enzyme glycogen synthase, which converts glucose to glycogen, thereby lowering blood glucose. Other proteins activated by the insulin receptor act to inhibit the synthesis of enzymes involved in making glucose, and to increase the number o glucose transporter proteins in the plasma membrane.
Insulin secretion is controlled by a complex set of factors that include, not only glucose but amino acids, catecholamines, and intestinal hormones. (Mojsov “Insulinotropin: Glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas” (October 28, 1986)).
Insulin secretion may be influenced by hormonal mediators acting locally by paracrine mechanisms as well as by vagal, sympathetic and peptidergic innervation. In addition to the porposed metabolic, endocrine and nueral regulation of insulin secretion, there is evidence to support the existence of insulinotropic factors termed “incretin” that originate from the intestine. (Drucker “Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line” Proc. Natl. Acad. Sci, USA, vol. 84, pp. 3434-3438, May 1987).
Epinephrine (aka, adrenaline): has diverse effects on different cell types. The distinct effects of epinephrine on different cell types depend on each cell having the same receptor for the hormone, but responding with different signal transduction pathways. In the liver, cells are stimulated to mobilized glucose, while in the heart muscle cells contract more forcefully to increase blood flow. (the fright response is due to release of epienphrine, also called adrenaline, into the bloodstream. Epinephrine receptors in the liver produce cAMP thorugh the enzyme adenylyl cyclase. The cAMP produced activates protein kinases that promote the produciton of glucose from glycogen. In smooth muscle, epinephrine receptors can activate a different G protein that activates the IP3 generating enzyme phospholipase C. As a result, epinephrine sitmulation of smooth muscle results in IP3-regulated release of intracellular calcium, causing muscle contraction.
The sympathetic nervous system (SNS) plays a vital role in maintaining the homeostasis of the body by secreting different neurotransmitters like catecholamines, acetylcholine, glutamine, etc. Among all the neurotransmitters, categholamine has a very important and diversified role in the various organs. Catecholamines contain a categhol (3,4 dihydroxypheynl) group along with an amine group. John Jacob Abel, in 1897 first obtained a crystalline substance form the adrenal gland of sheep in an impure form that can regulated blood pressure, and he named it epinephrine. In 1900, Jokichi Takamine obtained a pure cyrstalline form of epinephrine. He patented it with the name adrenalin. British Approved Name (BAN) introduced the name “adrenaline” in the UK. US Approved Name (USAN) used the term “epinephrine” for this neurotransmitter in the USA. Adrenaline is synthesized form its precursor amino acid tyrosine; it is also synthesized form hepatic hydroxylation of another amino acid, phenylalanine. Synthesis of catecholamine beings with the rate limiting step governed by the enzyme tyrosine hydroxylase, which converts tyrosine into L-DOPA. Subsequently, L-DOPA is coverted to dopamine and then to norepinephrine by DOPA decarboxylase and dopoamine beta-hydroxylase, respectively. Dopamine beta-hydroxylase is a copper containg enzyem and requires ascorbic acid for its function. Both epinephrine and norepinephrine stimulate common receptors name adrenergic receptors. Structurally these receptors have seven hydrophobic transmembrane regions and an intracellular C-terminal domain and an extracellular N-terminalal domain, along with 3 intracellular and extracellular loops. All adrenergic receptros work through different G prtoeins like Gs, Gi,e tc. Beta2 adrenergic receptor is the most abundant and most widely studied adrengergic receptor. (lal, Role of adrenergic receptor signalling in neuroimmune communication” Current Research in Immunology, 2 (2021) 202-217).
Erythropoietin (EPO) is a hormone that belongs to the class of peptide hormones, which are molecules composed of amino acids that act as signaling molecules. It is a naturally occurring hormone which stimulates the production of red blood cells in the bone marrow through a process called erythropoiesis. The production of EPO is useful in treating blood disorders characterized by low hematocrit, which is a low ratio fo red blood cells to total blood cells. Erythropoeisis (EPO): is a process stimulated by the peptide hormone erythropoietin (EPO). Erythropoiesis is the process of red blood cell production, and EPO, produced by the kidneys, stimulates this process. When oxygen available in the blood decreases, the kidney converts a plasma protein into the hormone erythropoietin which stimualates the production of erythrocytes form the myeloid stem cells through a process called erythropoiesis.
Melanocyte-stimulating hormone (MSH) stimulates the snthesis and dispersion of melanin pigment, which darkens the epidermis of some fish, amphibians and reptibles and can control hair pigment color in mammals. It is a peptide hormone of the anterio pituitary.
Parathyroid hormone (PTH): raises blood calcium level by stimulating bone breakdown, stimualtes calcium reabsorption in kidneys and activates vitamin D. Its target tissue is the bone, kidneys and digestive tract.
Steroid Hormones:
Steroid hormones form a large class of compounds, including cortisol, estrogen, progresterone and testosterone, that share a common nonpolar structure. The nonpolar structure allows these hormones to cross the membrane and bind to intracellular receptors.
Steroids are lipids manufactured by enzymatic modifications of cholesterol. Steroid hormones can be subdivided into sex steroids, secreted by the testes, ovaries, placenta, and adrenal cortex, and corticosteroids (mineralocorticoids and cortisol), secreted only by the adrenal cortex.
Estrogens:
The hormone estrogen has different effects in uterine tissue than in mammary tissue. This differential response is meiated by coactivators and not by the presence or absence of a receptor in the two tissues. In mammary tissue, a critical coactivtor is lacking and the hormone-receptor complex instead interacts with another protein that acts to reduce gene expression. In uterine tissue, the coactivator is present, and can bind the hormone-receptor complex to turn on the expression of genes that encode prtoeins involved in prearing the uterus for pregnancy.
Glucocorticoids are steroid hormones produced from the cortex of adrenal glands. Glcocorticoids are important modualtors of brain function and hypothalamus-pituitary-adrenal (HPA)-axis activity. To reach their central target areas they have to enter the brain by passing the blood-brain barrier (BBB), a dynamic barrier that protects the brain from periopheral influences.
–Cortisol: is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. As medication, cortisol is called hydrocortisone.
Cortisol is a hormone that is produced by the adrenal glands, located on top of the kidneys. The pituitary gland, located in the brain, regulates the amount of cortisol released by the adrenal glands. Cortisol can increase levels of glucose in cells. A number of different genes involved in the synthesis of glucose have binding sties for the hormone receptor complex.
Cortisol prevents the release of substances in the body that cause inflammation. It is thus known to inhibit IL-12, IFN-gamma, IFN-alpha dn TNF-alpha by APCs and TH1 cells. It upregulates IL-4, IL-10 and IL-13 by TH2 cells. This resutls in a shift toward a Th2 immune response.
Testosterone: stimulates development of secondary sex characteristics in males and growh spurt at puberty.
Neural and Hormonal Regulation of the Digestive Tract: (see outline)
Hormonal Control of Osmoregulatory Functions:
Antidiuretic hormone (ADH): is produced by the hypothalamus and secreted by the posterior-pituitary gland. The primary stimulus for ADH secretion is an increase in the osmolarity of the blood plasma. When a person is dehydrated or eat salty food, the osmolarity of plasma increases. Osmoreceptors in the hypothalamus respond to the elevated blood osmolarity by sending increasing action potentials to the integration center (also in the hypothalamus). This, in turn, triggers a sensation of thirst and an increase in the secretion of ADH.
ADH causes the walls of the distal conveluted tubules and collecting ducts in the kidney to become more permeable to water. Water channels called aquaporins are contained within the membranes of intracellular vesicles in the epithelium of the distal convoluted tubules and collecting ducts; ADH stimulates the fusion of the vesicle membrane with the plasma membrane, similar to the process of exocytosis. The aquaporins are now in place and allow water to flow out of the tubules and ducts in response to the hypertonic condition in the renal medulla. This water is reabsorbed into the bloodstream.
When secretion of ADH is reduced, the plasma membrane pinches in (invaginates) to form new vesicles that contain aquaporins. This removes the aquaporins from the plasma membrne of the distal convoluted tubule and collecting duct, making them less permeable to water. Thus more water is excreted in urine.
A person who lacks ADH due to pituitary damage has the disorder known as diabetes insipidus and constantly excretes a large volume of dilute urine. Such a person is in danger of becoming severely dehydrated and succumbing to dangerously low blood plasma.
Homeostasis via ADH action is also affected by thanol and caffeine, both of which inhibit secretion of ADH. This is the basis for the dehydration that is the aftereffect of drinking too much alcohol.
Aldosterone & atrial natriuretic peptide (ANP) control Na+ concentration:
Sodium ions are the major solute in the blood plasma. When [Na+] falls, the blood osmolarity falls. This drop in osmolarity inhibits ADH (above) secretion causing more water to remain in the collecting duct for excretion in the urine. As a result, the blood volume and blood pressure decrease.
A decrease in extracellular Na+ also causes more water to be drawn into cells by osmosis, partially offsetting the drop in plasma osmolarity, but further decreasing blood volume and blood pressure. If Na+ deprivation is severe, the blood volume may fall so low that blood pressure is insufficient to sustain life. Many animals have a “salt hunger” and actively seek salt, such as when deer gather at “salt licks”.
A drop in blood Na+ concentration is normally compensated for by the kidneys under the influence of the hormone aldosterone, which is secreted by the adrenal cortex. Aldosterone stimulates the distal convoluted tubules and collecting ducts to reabsorb Na+, decreasing the excretion of Na+ in the urine. The reabsorption of Na+ is followed by reabsorption of Cl- and water, so aldosterone has the net effect of promoting the retention of both salt and water. It thus helps to main blood volume, osmolarity and pressure.
When blood flow is reduced, the juxtaglomerular apparatus responds by secreting the enzyme renin into the blood. Renin catalyzes the production of the polypetpide angiotensin I from the protein angiotensinogen. Angiotensin I is then converted by another enzyme into angiotensin II, which stimulates blood vessels to constrict and the adrenal cortex to secrete aldosterone. Thus, homeostasis of blood volume and pressure can be maintained by the activation of this renin-angiotensin-aldosterone system. In addition to stimulating Na+ reabsorption, aldosterone also promotes the secretion of K+ into the distal convoluted tubules and collecitng ducts. Consequently, aldosterone lwoers the blood K+ concentraiton, helping to main constant blood K+ levels in teh face of changing amounts of K+ in the diet. People who lack the ability to produce aldosterone will die if untreated becasue of the excessive loss of salt and water in the urine and the buildup of K+ in the blood.
The action of adlosterone in promoting salt and water retention is opposed by another hormone, atrial natriuretic peptide (ANP), which is secreted by the right atrium of the heart in response to an increased blood volume, which stretches the atrium. Under these conditions aldosterone secretion from teh adrenal cortex decreases, and ANP secretion incases, thus promoting the excetion of salt and water in the urine and lowering the blood volume.