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Physiology Ch 74 p881-892 Introduction to Endocrinology There exist several types of chemical messenger systems in the body 1. Neurotransmitters – released by axons into synapses to act locally to control nerve functions 2. Endocrine Hormones – released by glands into the blood and influence target cells elsewhere 3. Neuroendocrine Hormones – secreted by neurons into blood to influences cells elsewhere 4. Paracrines – secreted by cells into extracellular fluid and affect neighboring cells 5. Autocrines – secreted by cells into extracellular fluid to affect the same cells producing them 6. Cytokines – peptides secreted into extracellular fluid and can function as para- or autocrines a. Examples include interleukins, lymphokines, leptin, adipokines Three classes of hormones exist: 1. Proteins and Polypeptides – ant/post pituitary, pancreas, parathyroid gland 2. Steroids – secreted by adrenal cortex, ovaries, testes, and placenta 3. Amines – come from tyrosine, secreted by thyroid, adrenal medulla Gland/Tissue Hormone Functions Structure Hypothalamus Thyrotropin-releasing hormone (TRH) Corticotropin-releasing hormone (CRH) Secretion of thyroid-stimulating hormone + prolactin Peptide Release of adrenocorticotropic hormone (ACTH) Peptide Hypothalamus Growth Hormone Releasing Hormone (GHRH) Release of growth hormone Peptide Hypothalamus Inhibits release of growth hormone Peptide Release of Leutenizing (LH) and follicle-stimulating (FSH) horm. Peptide Inhibits release of prolactin Amine Anterior Pituitary Anterior Pituitary Anterior Pituitary Anterior Pituitary Growth hormone inhibitory hormone GHIH Gonadotropin-releasing hormone (GnRH) Dopamine/prolactin inhibiting factor (PIF) Growth Hormone TSH ACTH Prolactin Protein synthesis/growth Peptide Peptide Peptide Peptide Anterior Pituitary FSH Anterior Pituitary LH Posterior Pituitary Antidiuretic Hormone (ADH) Posterior Pituitary Oxytocin Adrenal Cortex Cortisol Thyroid Thyroid Adrenal Cortex Thyroxine (T4) and Triiodothyronine (T3) Calcitonin Aldosterone Adrenal Medulla Pancreas Norepinephrine/epinephrine Insulin (B cells) Hypothalamus Hypothalamus Hypothalamus Synthesis/thyroid hormones Synthesis/adrenocorticoids Development of breasts and milk production Growth of follicles in ovaries/sperm maturation Ovulation/testosterone synthesis, forms corpus luteum estrogen/progest. synthesis Increases H2O absorption in kidneys and vasoconstriction and increase BP Milk ejection from breasts and uterine contractions Metabolism of proteins, carbs, fats, anti-inflammatory effect Increases rates of chemical reactions/metabolic rate Deposition of Ca on Bones Increase renal Na absorption, K secretion and H secretion Sympathetic stimulation Glucose entry into cells Peptide Peptide Peptide Peptide Steroid Amine Peptide Steroid Amine Peptide Gland/Tissue Hormone Functions Structure Pancreas Parathyroid Gland Glucagon (α cells) Parathyroid Hormone (PTH) Synthesis of glucose in liver Peptide Peptide Testes Testosterone Ovaries Ovaries Estrogens Progesterone Placenta Human chorionic gonadotropin (HCG) Human Somatomammotropin Estrogens Progesterone Renin Placenta Placenta Placenta Kidney Stomach 1,25dihydrooxycholecaliferol Erythropoietin Atrial natriuretic Peptide (ANP) Gastrin Small Intestine Secretin Small Intestine Cholecystokinin (CCK) Adipocytes Leptin Kidney Kidney Heart Controls serum Ca concentration by absorbing Ca in gut and kidneys and releasing Ca from bones Development of male reproductive system and 2nd sex character. Female reproductive system, breasts Secretion of uterine milk and development of breast secretion Growth of corpus luteum and secretion of estrogens + progest. Steroid Steroid Steroid Peptide Promote development of fetal tissues as well as breasts Peptide Female reproduction Steroid Steroid Peptide Secretion of uterine milk…. Conversion of angiotensinogen to angiotensin I Increases intestinal absorption of Ca and bone mineralization Increases erythrocyte production Increases Na excretion by kidneys, reduces BP Stimulates HCl secretion by parietal cells Stimulates pancreatic acinar cells to secrete HCO3 and H2O Gallbladder contraction and release of pancreatic enzymes Inhibits appetite, stimulates thermogenesis Steroid Peptide Peptide Peptide Peptide Peptide Peptide Polypeptide Hormones Stored in Secretory Vesicles Until Needed – synthesized on the rough end of endoplasmic reticulum of endocrine cells -synthesized as inactive preprohormones that are cleaved to form prohormones in ER -transferred to golgi for packaging into vesicles, being cleaved here into hormones -vesicles stored in cytoplasm bound to cell membrane until secretion by exocytosis (fusion with memb.) -stimulus for exocytosis is usually cytosolic increase in Ca concentration by depolarization of membrane -Can also be caused by increased cAMP and kinase activity Steroid Hormones are Synthesized from Cholesterol and are NOT stored – lipid soluble consisting of three cyclohexyl rings and one cyclopentyl ring combined -very little hormone storage in endocrine cells, but large stores of cholesterol-esters can be stored in vacuoles in cytoplasm for quick steroid synthesis after a stimulus -cholesterol comes from plasma but can also be synthesized, and hormones can easily cross membrane Amine Hormones are Derived from Tyrosine – Thyroid and adrenal medullary hormones formed by enzymes in cytoplasmic compartments of glandular cells -thyroid hormones synthesized by thyroid and incorporated into macromolecule protein thyroglobulin, stored in follicles within thyroid gland -secretion occurs when amines are split from thyroglobulin and free hormones enter blood -In the blood, they combine with plasma proteins (thyroxine-binding globulin) slowly releasing hormones to tissues -Adrenal medulla forms epinephrine and norepinephrine, secreting 4x more epinephrine: taken up into preformed vesicles and stored until secreted by exocytosis into blood where they are in free form Hormone Secretion, Transport, and Clearance from the Blood – some hormones are secreted within seconds after a gland is stimulated (epinephrine/norepinephrine), and act within minutes. -Others, such as thyroxine and GH can take months for full effect Concentrations of Hormones in Circulating Blood – concentrations of hormones needed is low, can range from 1 picogram in each mL of blood to a few micrograms in each mL Negative Feedback Prevents Overactivity – hormones are closely controlled, mostly though negative feedback mechanisms. -After stimulus causes release of hormone, conditions or products resulting from action of that hormone suppress its further release -Only when target tissue activity rises to an appropriate level will feedback signals to endocrine gland be powerful enough to slow further secretion -Can occur at gene level, transcription, or translation Surges of Hormones Can Occur with Positive Feedback – positive feedback occurs when action of hormone causes more secretion of the hormone, such as with Luteinizing Hormone (LH) that occurs as a result of estrogen on anterior pituitary before ovulation. -LH is released causing more estrogen secretion, causing more LH until a point of negative feedback is reached Cyclic Variations Occur in Hormone Release – seasonal changes can influence hormone release apart from negative and positive feedback mechanisms, such as sleep, diurnal cycle, and age -due to changes in neural pathways involved in controlling hormone release Transport of Hormones in the Blood – Water-soluble hormones dissolved in plasma and transported to their sites of synthesis to target tissues to diffuse into capillaries, interstitial fluid and target cells -Steroid and Thyroid hormones circulate bound to plasma proteins and are not active until they dissociate from proteins Two factors can increase or decrease hormones in blood: 1. Rate of hormone secretion in blood 2. Rate of removal of hormone from blood (metabolic clearance rate) expressed in mL of plasma cleared of hormone per minute a. Calculate rate of disappearance of hormone and plasma concentration of hormone in blood b. Metabolic clearance rate = rate of disappearance / concentration of hormone -Hormones cleaved from plasma by several ways, including metabolic destruction by tissues, binding with tissues, excretion by liver into bile, and excretion by kidneys into urine -For some hormones, decreased metabolic clearance causes excessively high concentration, such as several steroid hormones when liver is diseased and not able to clear hormone into bile -Peptide hormones freely soluble and degraded by enzymes in blood and tissues to be excreted by kidneys and liver (half life for angiotensin II is 1 minute) -Hormones bound to plasma proteins are cleared at a much slower rate – adrenal steroids half life is 20100 minutes whereas thyroid hormones may be 1-6 days Mechanism of Hormone Action -First step of hormone’s action is binding to specific receptors on target cell, some on membrane and some inside the cytoplasm -binding of hormone to receptor initiates a cascade of reactions becoming more powerful -hormone receptors are large proteins and specific for a single hormone -can be found on cell surface (peptide, catecholamine), cytoplasm (steroid), and nucleus (thyroid) Hormone Receptors are Regulated – number of receptors does not remain constant, and can be inactivated or destroyed during course of function and later reactivated or resynthesized -Down-regulation can result from inactivation of some receptor molecules, inactivation of some intracellular protein signaling molecules, sequestration of receptor inside of cell away from membrane, destruction of receptors, and decreased production of receptors -Up-regulation of receptors and intracellular signaling proteins causes more sensitivity to hormone Intracellular Signaling After Hormone Activation – hormone-receptor complex changes function of receptor to activate hormonal effects 1. Ion Channel-Linked receptors – all neurotransmitters such as acetylcholine and norepinephrine combine with receptors postsynaptically causing conformational changes and opening or closing of receptors for Na, K, Ca, or others, causing flow through and subsequent downstream effects 2. G Protein-linked Hormone Receptors – many hormones activate receptors coupled with heterotrimeric GTP-binding proteins (G proteins) which all have 7 transmembrane segments that loop in and out of cell membrane a. Intracellular components include three subunits, α, β, and γ. b. When hormone binds extracellular receptor, conformation change activates G protein to open close ion channels or change activity of enzymes in the cell c. G proteins can bind guanosine nucleotides. In inactive state, α, β, and γ complex binds GDP on α subunit d. Upon receptor binding, conformational change causes exchange of GDP for GTP, causing α subunit dissociation from complex and associate with other intracellular signaling molecules such as adenylyl cyclase or phospholipase C. e. Signaling is terminated when hormone is removed and α subunit inactivates by converting GTP to GDP and combines with β and γ subunits to make the complex -G proteins can be inhibitory or stimulatory depending on the hormone Enzyme-Linked Hormone Receptors – some receptors function as enzymes when activated -have 1 membrane spanning domain, outside binds hormone, inside has catalytic domain Leptin receptor is an example of Enzyme-linked hormone receptor, signaling occurs through a tyrosine kinase of the janus kinase (JAK) family, JAK2. Receptor exists as dimer 1. Binding of leptin to receptor causes conformational change enabling phosphorylation and activation of JAK2 2. JAK2 then phosphorylate other tyrosine residues within Leptin receptor-JAK2 complex such as STAT proteins, which when phosphorylated, activate transcription by leptin target genes to initiate protein synthesis 3. Phosphorylation of JAK2 also leads to activation of other pathways such as MAPK and PI3K pathways -Another example used in hormonal control is the receptor that when activated becomes an adenylyl cyclase in the interior of cell to catalyze formation of cAMP which acts as a second messenger -Few peptide hormones such as atrial natriuretic peptide uses cGMP as a second messenger Intracellular Receptors and Activation of Genes – Lipid soluble hormones such as steroid, adrenal, gonadal, thyroid, retinoid, and vitamin D can cross cell membrane to bind receptors inside the cell -The hormone-receptor complex binds a specific regulatory promoter sequence on DNA called the hormone response element and activates or represses transcription. Second Messenger Mechanisms for Mediating Hormonal Functions – in addition to cAMP, calmodulin and phospholipid breakdown products at as second messengers 1. cAMP Second Messenger – binding of hormone to receptor couples receptor to Gs (stimulatory) protein which stimulates adenylyl cyclase-cAMP system, which catalyzes converstion of ATP to cAMP inside cell. a. cAMP activates cAMP-dependent protein kinase to phosphorylate proteins inside cell b. Activates a cascade of enzymes, where one can activate multiple, and so forth. c. ACTH, calcitonin, catecholamines, CRH, FSH, glucagon, HCG, LH, PTH, etc.. use cAMP -if binding of hormone causes an inhibitory G protein cascade (Gi), adenylyl cyclase would be inhibited, causing reduced cAMP and reduced effects in cell -thyroid cell stimulated by cAMP forms thyroxine and triiodothyronine, whereas cAMP in adrenocortical cells causes secretion of adrenal steroid hormones -in renal tubules, cAMP increases their permeability to H2O 2. Phospholipid Second Messenger – some hormones activate transmembrane receptors to activate enzyme phospholipase C a. Phospholipase C catalyzes breakdown of membrane lipids such as phosphatidylinositol biphosphate (PIP2) into two second messengers inositol triphosphate (IP3) and diacylglycerol (DAG) b. IP3 mobilizes Ca ions from mitochondria and ER and act to contract smooth muscle and change cell secretion c. DAG activates protein kinase C (PKC), phosphorylating large number of proteins leading to a cellular response i. Lipid portion of DAG is arachidonic acid, precursor to prostaglandins and other local hormones 3. Calcium-Caldmodulin Second Messenger – Entry of Ca ions into cells is a second messenger and is initiated by changes in membrane potential with open Ca channels or a hormone interacting with membrane receptors to open channels a. Ca enters the cell and binds with the protein calmodulin (4 Ca sites on it). When 3-4 sites have been bound, calmodulin undergoes conformational change and initiates effects such as activation or inhibition of kinases b. Calmodulin-dependent kinases phosphorylate to cause activation or inhibition of proteins involved in cells response to hormone i. Calmodulin can activate Myosin light chain kinase, acting on smooth muscle to cause contraction -Normal Ca levels in cell are 10^-8 or 10^-7, not enough to activate calmodulin, which needs a concentration of 10^-6 or -5. This is the same amount of calcium required to activate troponin C in skeletal muscle Hormones that Act on Genetic Machinery – -Steroid hormones from adrenal cortex, ovaries, and testes cause synthesis of proteins in target cells to function as enzymes, transport or structural proteins 1. Steroid hormone diffuses across membrane and enters cytoplasm of cell to bind to receptor 2. Receptor-protein-hormone diffuses into nucleus and binds DNA to activate transcription 3. mRNA diffuses into cytoplasm to be translated on ribosomes in protein -Aldosterone is secreted by adrenal cortex enters cytoplasm of renal tubular cells and binds to mineralocorticoid receptor to promote Na reabsorption from tubules -Thyroid hormones increase transcription in the nucleus -thyroxine and triiodothyronine cause increased transcription of genes in nucleus by binding to receptors in nucleus called activated transcription factors within chromosomal complex -two important features of thyroid hormone function in nucleus are: 1. Activate genetic mechanisms for formation of intracellular proteins for metabolic activities 2. Once bound to intranuclear receptors, thyroid hormones continue to express their control for days or even weeks Measurement of Hormone Concentrations in Blood – uses sensitive method called the radioimmunoassay developed 45 years ago Radioimmunoassay – antibody specific for hormone is produced and mixed with fluid from animal containing hormone to be measured and simultaneously mixed with appropriate amount of purified standard hormone tagged with radioactive isotope -must be too little antibody to bind completely both radio-tagged and fluid. -natural hormone and tagged hormone compete for antibody -If large amount of radioactive hormone is found, it means there wasn’t as much natural hormone to compete with it from fluid, and vice versa Enzyme-linked Immunosorbent Assay – ELISA can measure almost any protein, combining antibodies with simple enzyme assays performed on plastic plates -plate has enzyme attached specific for hormone, samples are added to each wells followed by a second antibody also specific for hormone but binds to a different region on hormone -third antibody is added that recognizes the second antibody coupled to an enzyme that converts a suitable substrate to a product that can be detected by colorimetric or fluorescent methods