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Homeostasis Árpád Dobolyi Laboratory of Molecular and Systems Neurobiology, Department of Physiology and Neurobiology, Eötvös Loránd University Outline of the lecture 1. Internal environment of living organisms, homeostasis 2. Homeostatic regulations – endocrine system, hormones 3. Examples of homeostatic regulations not requiring the nervous system – Potassium level of blood plasma – Calcium level of blood plasma 4. Homeostatic regulations – nervous system – Elements of the nervous system – Hypothalamus 5. Examples of regulations involving the brain – Water balance The internal environment and its evolutionary origin • Intracellular space was formed by the appearance of cellular organisms (about 3 billion years ago). Its composition differed from that of the ancient ocean. • External environment was the sea whose composition was relatively stable. Each cell was in interaction with the sea, took up and released substances. • With the appearance of multicellular organisms, most of the cells are not in contact with the ocean, but rather the interstitial fluid. This is their internal environment (Claude Bernard: „milieu intérieur”, ~1840), whose composition resembles to that of the ancient ocean. • Subsequently, a circulatory system containing blood developed whose function is to connect the internal environment of different cells of the organism with each other and the external environment Transfer of substances in multicellular organisms Extracellular fluid • • Body cells are situated in watery internal environment through which life-sustaining exchanges are made Extracellular fluid (ECF): Fluid environment in which the cells live (fluid outside the cells) – Two components: • Plasma • Interstitial fluid • Intracellular fluid (ICF) - Fluid contained within all body cells Homeostasis • Defined as maintenance of a relatively stable internal environment (Walter Bradford Cannon, 1932, The Wisdom of the Body). - Homeostasis is essential for survival and function of all cells - Does not mean that composition, temperature, and other characteristics are absolutely unchanging • Interstitial fluid is in interaction with the blood. Thus, the organisms provide homeostasis through the regulation of the composition of the blood. Blood composition Suspension of cells in plasma (carrier fluid) 45% Cells 55% Plasma Formed elements (e.g. cells) Red cells (erythrocytes) 5x106/mL White cells (leukocytes) 7x103/mL Platelets (thrombocytes) 3x105/mL 99% < 1% Blood composition Blood Plasma • Straw colored clear liquid • Contains 90% water • 7% plasma proteins created in liver confined to bloodstream albumin maintain blood osmotic pressure immunoglobulins antibodies bind to foreign substances called antigens form antigen-antibody complexes fibrinogen for clotting • 2% other substances Nutrients, electrolytes, gases, hormones, waste products Formed Elements of Blood • Red blood cells (R.B.C.) • White blood cells (W.B.C.) granular leukocytes neutrophils eosinophils basophils agranular leukocytes lymphocytes - T cells, B cells, natural killer cells (N.K.C) monocytes • Platelets (special cell fragments) Functions of red blood cells 1. Transport oxygen from lungs to the tissues (oxyhemoglobin). 2. Transport carbon-di-oxide from tissues to lungs (carboxyhemoglobin) 3. Hemoglobin acts as a buffer and regulates the hydrogen ion concentration (acid base balance) 4. Carry the blood group antigens and Rh factor Ion concentrations within and outside a typical mammalian cell Some components of homeostasis Isoionia: homeostasis of ion concentrations and organic small molecules Ion concentrations in the blood plasma: Na+.......143 mmol/l Cl-..........................103 mmol/l K+.............4 mmol/l HCO3-.. ..................24 mmol/l Ca++......2,5 mmol/l H2PO4- és HPO4--…1 mmol/l Mg++.........1 mmol/l Some organic small compounds: Glocose….4.5-5.50 mmol/l Urea........2.5-6.3 mmol/l Isosmosis: Osmotic pressure of blood plasma: 290 milliosmol/l Isohidria: H-ion concentration: [H+]=35-40 nmol/l (pH: 7.38-7.42) Buffer systems: carbonates, phosphates, hemoglobin, plasma proteins Physical parameters: isovolume, isotermia Causes of deviation from homeostasis • Homeostasis is continually being disrupted by – External stimuli • heat, cold, lack of oxygen, pathogens, toxins – Internal stimuli • Body temperature • Blood pressure • Concentration of water, glucose, salts, oxygen, etc. • Physical and psychological distresses • Disruptions can be mild to severe • If homeostasis is not maintained, death may result Homeostatic control systems In order to maintain homeostasis, control system must be able to – Detect deviations from normal in the internal environment that need to be held within narrow limits – Integrate this information with other relevant information – Respond: make appropriate adjustments in order to restore factor to its desired value (set point) Temperature regulation by thermostat Temporal change of temperature as a result of regulation by thermostat Classification of homeostatic control systems Based on location: - Intrinsic controls: • Local controls that are inherent in an organ - Extrinsic controls • Regulatory mechanisms initiated outside an organ • Accomplished by endocrine and nervous systems Based on mechanism: - Feedforward - term used for responses made in anticipation of a change - Feedback - refers to responses made after change has been detected • Negative: original stimulus reversed • Positive: original stimulus intensified Feedback Loop • Receptor - structures that monitor a controlled condition and detect changes • Control center - determines next action • Effector – receives directions from the control center – produces a response that restores the controlled parameter Example of negative feedback loop to control blood glucose concentration • Blood glucose concentrations rise after a sugary meal (the stimulus), the hormone insulin is released and it speeds up the transport of glucose out of the blood and into selected tissues (the response), so blood glucose concentrations decrease (thus decreasing the original stimulus). Homeostasis of blood pressure • Baroreceptors in walls of blood vessels detect an increase in blood pressure • Brain receives input and signals blood vessels and heart • Blood vessels dilate, heart rate decreases • Blood pressure decreases Positive feedback during childbirth • Stretch receptors in walls of uterus send signals to the brain • Brain induces release of hormone (oxytocin) into bloodstream • Uterine smooth muscle contracts more forcefully • More stretch, more hormone, more contraction etc. • Cycle ends with birth of the baby & decrease in stretch Outline of the lecture 1. Internal environment of living organisms, homeostasis 2. Homeostatic regulations – endocrine system, hormones 3. Examples of homeostatic regulations not requiring the nervous system – Potassium level of blood plasma – Calcium level of blood plasma 4. Homeostatic regulations – nervous system – Elements of the nervous system – Hypothalamus 5. Examples of regulations involving the brain – Water balance Hormones – organic biologically active compounds of different chemical nature that are produced by the endocrine glands, enter directly into blood and accomplish humoral regulation of the metabolism of compounds and functions on the organism level. Hormonoids (tissue hormones) – compounds that are produced not in glands but in different tissues and regulate metabolic processes on the local level, but some of them (serotonin, acetylcholine) enters blood and regulate processes on the organism level. Four methods of cell-to-cell communication ranging from direct to remote communication Endocrine system • Endocrine system is composed of a number of glands, which are specialized tissues that produce hormones • Features of the endocrine system: 1. 2. 3. 4. Endocrine glands have a rich supply of blood Hormones, produced by the endocrine glands are secreted into the bloodstream Hormones travel in the blood to target cells close by or far away from point of secretion Hormone receptors are specific binding sites on the target cell Endocrine glands 1. Hypothalamus 2. Pituitary 3. Epiphysis (pineal gland) 4. Thyroid (and parathyroid gland) 5. Thymus 6. Adrenal gland 7. Langergans’ islands of pancreas 8. Sex glands (ovary or testis) Chemical nature of hormones Examples of different types of chemical signals used for cell-to-cell communication Secretion of hormones into the blood • Peptide and protein hormones are secreted by exocytosis • Steroid (lipophilic) hormones continuously penetrate the membrane -they are not accumulated in cells -their concentration in blood is determined by the speed of synthesis) Protein and peptide hormones are synthesized into the endoplasmic reticulum Figure 15-14 Essential Cell Biology (© Garland Science 2010) Functions of different parts of the Golgi apparatus Constitutive and regulated exocytosis The mechanism of exocytosis of protein and peptide hormones Electromicroscopic image of insulin sscretion Posttranslational modification of peptide hormones Examples of the position of peptide hormones in the newly synthesized protein chains Cleavage of prohormones by endopeptidases (prohormon convertases) in the Golgi apparatus Transport of hormones in blood • Proteins and peptides – in free state • Steroid hormones and hormones of thyroid gland – bound with alpha-globulins or albumins • Catecholamines – in free state or bound with albumins, sulphates or glucuronic acid • Reach the target organs • Cells have the specific receptors to certain hormone Hormones act where they have receptors Target cells Target cells refer to cells that contain specific receptors (binding sites) for a particular hormone. Once a hormone binds to receptors on a target cell, a series of cellular events unfold that eventually impact gene expression and protein synthesis. Action of steroid hormones • Steroid hormones enter through the cell membrane and bind to receptors inside of the target cell • These hormones may directly stimulate transcription of genes to make certain proteins • Because steroids work by triggering gene activity, the response is slower than peptide hormones Receptors of steroid hormones steroid hormone (extracellular fluid) 2 The hormone binds to a receptor in the nucleus or to a receptor in the cytoplasm that carries it into the nucleus 3 The hormone–receptor complex binds to DNA and causes RNA polymerase to bind to a nearby promoter site for a specific gene 1 A steroid hormone diffuses through the plasma membrane plasma membrane DNA hormone receptor ribosome RNA polymerase 5 The mRNA leaves the nucleus, then attaches to a ribosome and directs the synthesis of a specific protein product mRNA 4 RNA polymerase catalyzes the transcription of DNA into messenger RNA (mRNA) gene new protein nuclear envelope (cytoplasm) (nucleus) Action of protein/peptide hormones • Protein/peptide hormones do not enter the cell directly. These hormones bind to receptor proteins in the cell membrane. • When the hormone binds with the receptor protein, a secondary messenger molecule initiates the cell response • Protein/peptide hormones often produce fast responses Receptors of peptide hormones peptide or amino acid-derived hormone (first messenger) 1 The hormone binds to a receptor on the plasma membrane of a target cell (extracellular fluid) receptor 2 Hormone–receptor binding activates an enzyme that catalyzes the synthesis of a second messenger, such as cyclic AMP cyclic AMPsynthesizing (cytoplasm) enzyme ATP active enzyme product cyclic AMP (second messenger) 4 The activated enzymes catalyze specific reactions plasma membrane inactive enzyme reactant 3 The second messenger activates other enzymes nuclear envelope (nucleus) Types of membrane-bound receptors Inactivation of hormones • • Hormones are eventually broken down (metabolized) and/or excreted from the body The rate of removal from the circulation is fairly constant for a given hormone The length of time it takes to remove half of the amount of hormone from the circulation is the half-life of that hormone. 100% Amount of Hormone • 50% 0% Time Inactivation of hormones 2 Hormones are inactivated mainly in liver Inactive metabolites are excreted mainly with urine Half-time life - from several min to 20 min – for the majority of hormones - till 1 h – for steroid hormones - till 1 week – for thyroid hormones Outline of the lecture 1. Internal environment of living organisms, homeostasis 2. Homeostatic regulations – endocrine system, hormones 3. Examples of homeostatic regulations not requiring the nervous system – Potassium level of blood plasma – Calcium level of blood plasma 4. Homeostatic regulations – nervous system – Elements of the nervous system – Hypothalamus 5. Examples of regulations involving the brain – Water balance Some components of homeostasis Isoionia: homeostasis of ion concentrations and organic small molecules Ion concentrations in the blood plasma: Na+.......143 mmol/l Cl-..........................103 mmol/l K+.............4 mmol/l HCO3-.. ..................24 mmol/l Ca++......2,5 mmol/l H2PO4- és HPO4--…1 mmol/l Mg++.........1 mmol/l Some organic small compounds: Glocose….4.5-5.50 mmol/l Urea........2.5-6.3 mmol/l Isosmosis: Osmotic pressure of blood plasma: 290 milliosmol/l Isohidria: H-ion concentration: [H+]=35-40 nmol/l (pH: 7.38-7.42) Buffer systems: carbonates, phosphates, hemoglobin, plasma proteins Physical parameters: isovolume, isotermia Potassium homeostasis • Blood plasma concentration: 3.6-5.0 mmol/l • Excretion: 90% kidney, 10% gut • Causes of low potassium ion level: - reduced oral intake - intestinal loss: diarrhea, vomiting - renal loss: kidney disease Consequence: Ki/Ke muscles cannot properly contract • Causes of high potassium ion level : - increased potassium intake (combined with kodney disease) - reduced excretion in kidney (e.g. due to digitalis poisining) - potassium loss from cells (trauma, hemolysis, cytostatics) Consequence: : Elevated excitability of muscles: spasms of sceletal muscles, and cardiac problems Passive regulation of blood plasma potassium from „internal store” Passive control: extracellular K-ion level acts on the activity of Na-K pump and potassium channels present in the plasmamembrane of all cells. Small relative change of the intracellular potassium level, which has no effect on intracellular processes, can significantly compensate the smaller level of potassium in the extracellular space Compartments interacting with the blood: potential surfaces of regulations • Gastrointestinal tract - Behaviors determining feeding and drinking - Regulation of absorption - Secretion with faces • Kidney • Lung (mostly for gases) • Sweat • Internal stores - Binding proteins in the blood - Intracellular space of the cells - Organs specialized for storage Nephron Reabsorption in the proximal convoluted tubule Nephron Reabsorption in the distal convoluted tubule and the collecting duct Hormonally regulated active control of blood potassium ion level - 92% of potassium ion of the primary urine is reabsorbed before the collecting duct - There is a low speed non-controlled potassium ion reabsorption in the medully, which reabsorbes all potassium ion leading to zero excretion without regulation - Active regulation: aldosterone, a mineralocorticoid steroid hormone released from the adrenal gland leads to increased secretion of potassium in the initial segment of the collecting duct thereby reducing blood plasma potassium ion level. This is the only active regulation of potassium level of the blood. - Regulation has only one direction, and is not very strong but still sufficient as passive regulation helps out and potassium intake with food is relatively constant in the long term. Potassium does not even have a specific taste as sodium ion determines primarily the salty taste. Mechanism of action of aldosterone Aldosterone increases the activity of the Na-K pump thereby increasing intracellular potassium ion level, which leads to its secretion to the lumen of the collecting tube. Endocrine glands 1. Hypothalamus 2. Pituitary 3. Epiphysis (pineal gland) 4. Thyroid (and parathyroid gland) 5. Thymus 6. Adrenal gland 7. Langergans’ islands of pancreas 8. Sex glands (ovary or testis) Adrenal gland Mineralocorticoids Glucocorticoids Sexual steroids Catecholamines Synthesis and regulation of aldosterone secretion Outline of the lecture 1. Internal environment of living organisms, homeostasis 2. Homeostatic regulations – endocrine system, hormones 3. Examples of homeostatic regulations not requiring the nervous system – Potassium level of blood plasma – Calcium level of blood plasma 4. Homeostatic regulations – nervous system – Elements of the nervous system – Hypothalamus 5. Examples of regulations involving the brain – Water balance Calcium content of human Total body calcium = 1500 g Bone 99% Intracellular Ca 0.9% Interstitial Ca 0.075% Plasma Ca 0.025% Plasma Ca: Bound to proteins– 45% In complexes– 10% Ionized free Ca – 45% Biologically active fraction Calcium homeostasis Daily Ca intake 1000 mg 200 mg 400 mg Extracellular calcium (1500 mg) 200 mg 200 mg 10.000 mg 9.800 mg 800 mg 200 mg Endocrine glands 1. Hypothalamus 2. Pituitary 3. Epiphysis (pineal gland) 4. Thyroid (and parathyroid gland) 5. Thymus 6. Adrenal gland 7. Langergans’ islands of pancreas 8. Sex glands (ovary or testis) Regulatory hormones of calcium homeostasis The major regulatory hormone is parathyroid hormone (PTH), which increases calcium ion level in the plasma. PTH is produced in the parathyroid gland when blood calcium ion levels decrease. Another hormone, calcitonin has the opposite effects, it increases plasma calcium ion level. Calcitonin is produced in C cells of the thyroid hormone. Calcium receptor senses calcium ion level in the plasma Intracellular signaling of calcium receptor PTH secretion is inhibited Calcitonon secretion is stimulated Target tissues of hormones regulating plasma calcium ion level Parathyroid hormone: • • • kidney – Stimulates calcium ion reabsorption – Stimulates the synthesis of vitamin D bone – Stimulates osteolysis Gastrointestinal system – No direct effect – Vitamin D increases the absorption of calcium iom in the small intestine Calcitonin: • bone – Inactivates osteoclasts thereby inhibits osteolysis Regulation of calcium homeostasis Daily Ca intake 1000 mg Calcitonin 200 mg 400 mg extracellular calcium (1500mg) 200 mg 200 mg 10.000 mg 800 mg 9.800 mg PTH Vitamin D 200 mg Comparison of the regulation of plasma calcium to that of potassium ion • Parathyroid hormone increases calium ion level while aldosterone descreases potassium ion level, so the major direction of regulation is the opposite • Calcium ion level can be regulated in both direction as not only parathyroid hormone but also calcitonin plays a role, which has opposite effect on plasma calcium level • Parathyroid hormone acts to increase calcium ion levels in 3 different tissues while aldosterone regulates potassium ion level only in the kidney • Parathyroid hormone has indirect effects, too. It includes another hormone, vitamin D in the control of plasma Ca ion level • Both regulation is coupled (potassium to sodium, calcium to phosphate), both opposing directions • Neither regulations involves the nervous system