Pocket Companion to Guyton and Hall Textbook of Medical Physiology PDF

VetBooks.ir VetBooks.ir Any screen. n. Any time. Anywhere. Activate the eBook version rge. of this title at...

VetBooks.ir VetBooks.ir Any screen. n. Any time. Anywhere. Activate the eBook version rge. of this title at no additional charge. Student Consult eBooks give you the power to browse and find content, view enhanced images, share notes and highlights—both online and offline. Unlock your eBook today. 1 Visit studentconsult.inkling.com/redeem 2 Scratch off your code 3 Type code into “Enter Code” box Scan this QR code to redeem your eBook through your mobile device: 4 Click “Redeem” 5 Log in or Sign up 6 Go to “My Library” It’s that easy! FPO: Peel Off Sticker For technical assistance: email [email protected] call 1-800-401-9962 (inside the US) call +1-314-447-8200 (outside the US) Use of the current edition of the electronic version of this book (eBook) is subject to the terms of the nontransferable, limited license granted on studentconsult.inkling.com. Access to the eBook is limited to the first individual who redeems the PIN, located on the inside cover of this book, at studentconsult.inkling.com and may not be transferred to another party by resale, lending, or other means.  GUYTON VetBooks.ir AND HALL The world’s foremost medical physiology resources Guyton and Hall Textbook of Medical Physiology, 13th Edition John E. Hall, PhD 978-1-4557-7005-2 Unlike other physiology textbooks, this clear and comprehensive guide has a consistent, single-author voice and focuses on the content most relevant to clinical and pre-clinical students. The detailed but lucid text is complemented by didactic illustrations that summarize key concepts in physiology and pathophysiology. Pocket Companion to Guyton and Hall Textbook of Medical Physiology, 13th Edition John E. Hall, PhD 978-1-4557-7006-9 Guyton and Hall Physiology Review, 3rd Edition John E. Hall, PhD 978-1-4557-7007-6 ORDER TODAY! elsevierhealth.com VetBooks.ir NOTE TO INSTRUCTORS: Contact your Elsevier Sales Representative for teaching resources, including slides and image banks, for Guyton and Hall Textbook of Medical Physiology, 13e, or request these supporting materials at: http://evolve.elsevier.com/Hall13  Pocket Companion to Guyton and Hall Textbook of Medical Physiology VetBooks.ir Thirteenth Edition John E. Hall, PhD Arthur C. Guyton Professor and Chair Department of Physiology and Biophysics Director of the Mississippi Center for Obesity Research University of Mississippi Medical Center Jackson, Mississippi  1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 POCKET COMPANION TO GUYTON AND ISBN: 978-1-4557-7006-9 HALL TEXTBOOK OF MEDICAL PHYSIOLOGY, THIRTEENTH EDITION Copyright © 2016 by Elsevier, Inc. All rights reserved. VetBooks.ir No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Pub- lisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copy- right by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new re- search and experience broaden our understanding, changes in research meth- ods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of admin- istration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, con- tributors, or editors, assume any liability for any injury and/or damage to per- sons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2012, 2006, 2001, 1998 by Saunders, an imprint of Elsevier, Inc. Library of Congress Cataloging-in-Publication Data Hall, John E. (John Edward), 1946- , author. Pocket companion to Guyton and Hall textbook of medical physiology / John E. Hall. -- Thirteenth edition. p. ; cm. Complemented by: Guyton and Hall textbook of medical physiology / John E. Hall. Thirteenth edition.. Includes index. ISBN 978-1-4557-7006-9 (paperback : alk. paper) I. Hall, John E. (John Edward), 1946- Guyton and Hall textbook of medical physiology. Complemented by (expression): II. Title. [DNLM: 1. Physiological Phenomena. QT 104] QP35 612--dc23 2015002946 Senior Content Strategist: Elyse O’Grady Senior Content Development Manager: Rebecca Gruliow Publishing Services Manager: Patricia Tannian Senior Project Manager: Carrie Stetz Design Direction: Julia Dummitt Printed in The United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1  Contributors Thomas H. Adair, PhD VetBooks.ir Professor of Physiology and Biophysics University of Mississippi Medical Center Jackson, Mississippi Membrane Physiology, Nerve, and Muscle (Chapters 4–8) Respiration (Chapters 38–43) Aviation, Space, and Deep-Sea Diving Physiology (Chapters 44–45) The Nervous System: A. General Principles and Sensory Physiology (Chapters 46–49) The Nervous System: B. The Special Senses (Chapters 50–54) The Nervous System: C. Motor and Integrative Neurophysiology (Chapters 55–60) Gastrointestinal Physiology (Chapters 63–67) John E. Hall, PhD Arthur C. Guyton Professor and Chair Department of Physiology and Biophysics Director, Mississippi Center for Obesity Research University of Mississippi Medical Center Jackson, Mississippi Introduction to Physiology: The Cell and General Physiology (Chapters 1–3) The Circulation (Chapters 14–19) The Body Fluids and Kidneys (Chapters 25–32) Blood Cells, Immunity, and Blood Coagulation (Chapters 33–37) The Nervous System: C. Motor and Integrative Neurophysiology (Chapters 61–62) Metabolism and Temperature Regulation (Chapters 68–74) Endocrinology and Reproduction (Chapters 80–84) Sports Physiology (Chapter 85) Thomas E. Lohmeier, PhD Professor Emeritus of Physiology and Biophysics University of Mississippi Medical Center Jackson, Mississippi Endocrinology and Reproduction (Chapters 75–79) R. Davis Manning, PhD Professor Emeritus of Physiology and Biophysics University of Mississippi Medical Center Jackson, Mississippi The Heart (Chapters 9–13) The Circulation (Chapters 20–24) v  This page intentionally left blank VetBooks.ir        Preface Human physiology is the discipline that links the basic VetBooks.ir sciences with clinical medicine. It is integrative and encompasses the study of molecules and subcellular components, cells, tissues, and organ systems, as well as the feedback systems that coordinate these compo- nents of the body and permit us to function as living beings. Because human physiology is a rapidly expand- ing discipline and covers a broad scope, the vast amount of information that is applicable to the practice of medi- cine can be overwhelming. Therefore, one of our major goals for writing this Pocket Companion was to distill this enormous amount of information into a book that would be small enough to be carried in a coat pocket and used often but still contain most of the basic physi- ological principles necessary for the study of medicine. The Pocket Companion was designed to accompany Guyton and Hall Textbook of Medical Physiology, 13th Edition, not substitute for it. It is intended to serve as a concise overview of the most important facts and con- cepts from the parent text, presented in a manner that facilitates rapid comprehension of basic physiological principles. Some of the most important features of the Pocket Companion are as follows: It was designed to serve as a guide for students who wish to review a large volume of material from the parent text rapidly and efficiently. The headings of the sections state succinctly the primary concepts in the accompanying paragraphs. Thus, the student can quickly review many of the main concepts in the textbook by first studying the paragraph headings. The table of contents matches that of the parent text, and each topic has been cross-referenced with spe- cific page numbers from the parent text. The pocket companion has been updated in parallel with the Textbook of Medical Physiology, 13th edition. The size of the book has been restricted so it can fit conveniently in a coat pocket as an immediate source of information. Although the Pocket Companion contains the most important facts necessary for studying physiology, it does not contain the details that enrich the physiological concepts or the clinical examples of abnormal physiol- ogy that are contained in the parent book. We therefore recommend that the Pocket Companion be used in con- junction with the Textbook of Medical P ­ hysiology, 13th Edition. vii  viii Preface I am grateful to each of the contributors for their careful work on this book. Contributing authors were selected for their knowledge of physiology and their VetBooks.ir ability to present information effectively to students. We also greatly appreciate the excellent work of Rebecca Gruliow, Elyse O’Grady, Carrie Stetz, and the entire Elsevier team for continued editorial and production excellence. We have strived to make this book as accurate as possible and hope that it will be valuable for your study of physiology. Your comments and suggestions for ways to improve the Pocket Companion are always greatly appreciated. John E. Hall, PhD Jackson, Mississippi  Contents UNIT I VetBooks.ir Introduction to Physiology: The Cell and General Physiology CHAPTER 1 F unctional Organization of the Human Body and ­Control of the “Internal Environment,” 3 CHAPTER 2 The Cell and Its Functions, 9 CHAPTER 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction, 19 UNIT II  embrane Physiology, Nerve, and Muscle M CHAPTER 4 Transport of Substances Through Cell Membranes, 31 CHAPTER 5 Membrane Potentials and Action Potentials, 38 CHAPTER 6 Contraction of Skeletal Muscle, 44 CHAPTER 7 Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling, 51 CHAPTER 8 Excitation and Contraction of Smooth Muscle, 55 UNIT III The Heart CHAPTER 9  ardiac Muscle; The Heart as a Pump and Function of C the Heart Valves, 63 CHAPTER 10 Rhythmical Excitation of the Heart, 71 CHAPTER 11 The Normal Electrocardiogram, 76 ix  x Contents CHAPTER 12 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial VetBooks.ir Analysis, 79 CHAPTER 13 Cardiac Arrhythmias and Their Electrocardiographic Interpretation, 84 UNIT IV The Circulation CHAPTER 14 Overview of the Circulation; Biophysics of Pressure, Flow, and Resistance, 91 CHAPTER 15 Vascular Distensibility and Functions of the Arterial and Venous Systems, 97 CHAPTER 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow, 103 CHAPTER 17 Local and Humoral Control of Tissue Blood Flow, 113 CHAPTER 18 Nervous Regulation of the Circulation and Rapid Control of Arterial Pressure, 123 CHAPTER 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension: The Integrated System for Arterial Pressure Regulation, 131 CHAPTER 20 Cardiac Output, Venous Return, and Their Regulation, 142 CHAPTER 21 Muscle Blood Flow and Cardiac Output During Exercise; the Coronary Circulation and Ischemic Heart Disease, 148 CHAPTER 22 Cardiac Failure, 154 CHAPTER 23 Heart Valves and Heart Sounds; Valvular and Congenital Heart Defects, 160  Contents xi CHAPTER 24 Circulatory Shock and Its Treatment, 165 VetBooks.ir UNIT V T he Body Fluids and Kidneys CHAPTER 25 T he Body Fluid Compartments: Extracellular and Intracellular Fluids; Edema, 175 CHAPTER 26 T he Urinary System: Functional Anatomy and Urine Formation by the Kidneys, 185 CHAPTER 27  lomerular Filtration, Renal Blood Flow, and Their G Control, 192 CHAPTER 28 Renal Tubular Reabsorption and Secretion, 198 CHAPTER 29  rine Concentration and Dilution; Regulation U of Extracellular Fluid Osmolarity and Sodium Concentration, 209 CHAPTER 30  enal Regulation of Potassium, Calcium, Phosphate, R and Magnesium; Integration of Renal Mechanisms for Control of Blood Volume and Extracellular Fluid Volume, 218 CHAPTER 31 Acid-Base Regulation, 230 CHAPTER 32 Diuretics, Kidney Diseases, 241 UNIT VI Blood Cells, Immunity, and Blood Coagulation CHAPTER 33 Red Blood Cells, Anemia, and Polycythemia, 251 CHAPTER 34  esistance of the Body to Infection: I. Leukocytes, R Granulocytes, the Monocyte-Macrophage System, and Inflammation, 256  xii Contents CHAPTER 35  esistance of the Body to Infection: II. Immunity and R Allergy, 262 VetBooks.ir CHAPTER 36  lood Types; Transfusion; Tissue and Organ B Transplantation, 270 CHAPTER 37 Hemostasis and Blood Coagulation, 273 UNIT VII Respiration CHAPTER 38 Pulmonary Ventilation, 281 CHAPTER 39  ulmonary Circulation, Pulmonary Edema, Pleural P Fluid, 288 CHAPTER 40 Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide Through the Respiratory Membrane, 294 CHAPTER 41 T ransport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids, 302 CHAPTER 42 Regulation of Respiration, 308 CHAPTER 43 Respiratory Insufficiency—Pathophysiology, Diagnosis, Oxygen Therapy, 312 UNIT VIII Aviation, Space, and Deep-Sea Diving Physiology CHAPTER 44 Aviation, High Altitude, and Space Physiology, 321 CHAPTER 45  hysiology of Deep-Sea Diving and Other Hyperbaric P Conditions, 326  Contents xiii UNIT IX The Nervous System: A. General Principles and Sensory Physiology VetBooks.ir CHAPTER 46  rganization of the Nervous System, Basic Functions O of Synapses, and Neurotransmitters, 333 CHAPTER 47  ensory Receptors, Neuronal Circuits for Processing S Information, 340 CHAPTER 48 Somatic Sensations: I. General Organization, the Tactile and Position Senses, 345 CHAPTER 49  omatic Sensations: II. Pain, Headache, and Thermal S Sensations, 352 UNIT X The Nervous System: B. The Special Senses CHAPTER 50 The Eye: I. Optics of Vision, 361 CHAPTER 51 T he Eye: II. Receptor and Neural Function of the Retina, 366 CHAPTER 52 The Eye: III. Central Neurophysiology of Vision, 375 CHAPTER 53 The Sense of Hearing, 381 CHAPTER 54 The Chemical Senses—Taste and Smell, 387 UNIT XI The Nervous System: C. Motor and Integrative Neurophysiology CHAPTER 55  otor Functions of the Spinal Cord; the Cord Reflexes, M 395 CHAPTER 56 Cortical and Brain Stem Control of Motor Function, 401  xiv Contents CHAPTER 57 Contributions of the Cerebellum and Basal Ganglia to Overall Motor Control, 410 VetBooks.ir CHAPTER 58  erebral Cortex, Intellectual Functions of the Brain, C Learning, and Memory, 421 CHAPTER 59  ehavioral and Motivational Mechanisms of the B Brain—The Limbic System and the Hypothalamus, 429 CHAPTER 60  tates of Brain Activity—Sleep, Brain Waves, S Epilepsy, Psychoses, and Dementia, 435 CHAPTER 61 T he Autonomic Nervous System and the Adrenal Medulla, 440 CHAPTER 62  erebral Blood Flow, Cerebrospinal Fluid, and Brain C Metabolism, 450 UNIT XII Gastrointestinal Physiology CHAPTER 63  eneral Principles of Gastrointestinal Function— G Motility, Nervous Control, and Blood Circulation, 459 CHAPTER 64 Propulsion and Mixing of Food in the Alimentary Tract, 466 CHAPTER 65 Secretory Functions of the Alimentary Tract, 471 CHAPTER 66  igestion and Absorption in the Gastrointestinal Tract, D 478 CHAPTER 67 Physiology of Gastrointestinal Disorders, 485  Contents xv UNIT XIII Metabolism and Temperature Regulation VetBooks.ir CHAPTER 68  etabolism of Carbohydrates and Formation of M Adenosine Triphosphate, 491 CHAPTER 69 Lipid Metabolism, 498 CHAPTER 70 Protein Metabolism, 506 CHAPTER 71 The Liver as an Organ, 510 CHAPTER 72  ietary Balances; Regulation of Feeding; Obesity and D Starvation; Vitamins and Minerals, 515 CHAPTER 73 Energetics and Metabolic Rate, 526 CHAPTER 74 Body Temperature Regulation and Fever, 529 UNIT XIV Endocrinology and Reproduction CHAPTER 75 Introduction to Endocrinology, 537 CHAPTER 76  ituitary Hormones and Their Control by the P Hypothalamus, 543 CHAPTER 77 Thyroid Metabolic Hormones, 553 CHAPTER 78 Adrenocortical Hormones, 561 CHAPTER 79 Insulin, Glucagon, and Diabetes Mellitus, 571 CHAPTER 80 Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth, 579 CHAPTER 81  eproductive and Hormonal Functions of the Male R (and Function of the Pineal Gland), 588  xvi Contents CHAPTER 82 F emale Physiology Before Pregnancy and Female Hormones, 593 VetBooks.ir CHAPTER 83 Pregnancy and Lactation, 602 CHAPTER 84 Fetal and Neonatal Physiology, 610 UNIT XV Sports Physiology CHAPTER 85 Sports Physiology, 617  UNIT I Introduction to Physiology: The Cell VetBooks.ir and General Physiology 1 Functional Organization of the Human Body and Control of the “Internal Environment,” 3 2 The Cell and Its Functions, 9 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction, 19  This page intentionally left blank VetBooks.ir        CHAPTER 1 Functional Organization of the Human Body and Control of the “Internal VetBooks.ir Environment” Physiology is the science that seeks to understand the function of living organisms and their parts. In human physiology, we are concerned with the characteristics of the human body that allow us to sense our environment, move about, think and communicate, reproduce, and perform all of the functions that enable us to survive and thrive as living beings. Human physiology is a broad subject that attempts to explain the specific characteristics and mecha- nisms of the human body that make it a living being. The subject includes the functions of molecules and subcellular components; tissues; organs; organ sys- tems, such as the cardiovascular system; and the interaction and communication among these compo- nents. A distinguishing feature of physiology is that it seeks to integrate the functions of all of the parts of the body to understand the function of the entire human body. Life in the human being relies on this total function, which is considerably more complex than the sum of the functions of the individual cells, tissues, and organs. Cells Are the Living Units of the Body. Each organ is an aggregate of many cells held together by intercellular supporting structures. The entire body contains about 100 trillion cells, each of which is adapted to perform special functions. These individual cell functions are coordinated by multiple regulatory systems operating in cells, tissues, organs, and organ systems. Although the many cells of the body differ from each other in their special functions, all of them have certain basic characteristics. For example, (1) oxygen combines with breakdown products of fat, carbohy- drates, or protein to release energy that is required for function of the cells; (2) most cells have the abil- ity to reproduce, and whenever cells are destroyed, the remaining cells often regenerate new cells until the appropriate number is restored; and (3) cells are bathed in extracellular fluid, the constituents of which are precisely controlled. 3  4 UNIT I Introduction to Physiology: The Cell and General Physiology MECHANISMS OF HOMEOSTASIS— MAINTENANCE OF NEARLY CONSTANT INTERNAL ENVIRONMENT (p. 4) VetBooks.ir Essentially all the organs and tissues of the body per- form functions that help maintain the constituents of the extracellular fluid so they are relatively stable, a condition called homeostasis. Much of our discussion of physiology focuses on mechanisms by which the cells, tissues, and organs contribute to homeostasis. Extracellular Fluid Transport and Mixing System—The Blood Circulatory System Extracellular fluid is transported throughout the body in two stages. The first stage is movement of blood throughout the circulatory system, and the second stage is movement of fluid between the blood capil- laries and cells. The circulatory system keeps the flu- ids of the internal environment continuously mixed by pumping blood through the vascular system. As blood passes through the capillaries, a large portion of its fluid diffuses back and forth into the intersti- tial fluid that lies between the cells, allowing continu- ous exchange of substances between the cells and the interstitial fluid and between the interstitial fluid and the blood. Origin of Nutrients in the Extracellular Fluid The respiratory system provides oxygen for the body and removes carbon dioxide. The gastrointestinal system digests food and facili- tates absorption of various nutrients, including car- bohydrates, fatty acids, and amino acids, into the extracellular fluid. The liver changes the chemical composition of many of the absorbed substances to more us- able forms, and other tissues of the body (e.g., fat cells, kidneys, endocrine glands) help modify the absorbed substances or store them until they are needed. The musculoskeletal system consists of skeletal mus- cles, bones, tendons, joints, cartilage, and ligaments. Without this system, the body could not move to the appropriate place to obtain the foods required for nutrition. This system also protects internal organs and supports the body.  Functional Organization of the Human Body and Control of the 5 “Internal Environment” Removal of Metabolic End Products (p. 5) The respiratory system not only provides oxygen to VetBooks.ir the extracellular fluid but also removes carbon diox- ide, which is produced by the cells, released from the blood into the alveoli, and then released to the exter- nal environment. The kidneys excrete most of the waste products other than carbon dioxide. The kidneys play a ma- jor role in regulating extracellular fluid composition by controlling excretion of salts, water, and waste products of the chemical reactions of the cells. By controlling body fluid volumes and compositions, the kidneys also regulate blood volume and blood pressure. The liver eliminates certain waste products pro- duced in the body, as well as toxic substances that are ingested. Regulation of Body Functions The nervous system directs the activity of the muscular system, thereby providing locomotion. It also controls the function of many internal or- gans through the autonomic nervous system, and it a­ llows us to sense our external and internal en- vironment and to be intelligent beings so we can obtain the most advantageous conditions for sur- vival. The hormone systems control many metabolic func- tions of the cells, such as growth, rate of metabolism, and special activities associated with reproduction. Hormones are secreted into the bloodstream and are carried to tissues throughout the body to help regu- late cell function. Protection of the Body The immune system provides the body with a defense mechanism that protects against foreign invaders, such as bacteria and viruses, to which the body is exposed daily. The integumentary system, which is composed mainly of skin, provides protection against injury and defense against foreign invaders, as well as protection of underlying tissues against dehydra- tion. The skin also serves to regulate body temper- ature.  6 UNIT I Introduction to Physiology: The Cell and General Physiology Reproduction The reproductive system provides for formation of new VetBooks.ir beings like ourselves. Even this function can be consid- ered a homeostatic function because it generates new bodies in which trillions of additional cells can exist in a well-regulated internal environment. CONTROL SYSTEMS OF THE BODY (p. 6) The human body has thousands of control systems that are essential for homeostasis. For example, genetic systems operate in all cells to control intracellular and extracellular functions. Other control systems operate within the organs or throughout the entire body to con- trol interactions among the organs. Regulation of oxygen and carbon dioxide concentra- tions in the extracellular fluid is a good example of multi- ple control systems that operate together. In this instance, the respiratory system operates in association with the nervous system. When carbon dioxide concentration in the blood increases above normal, the respiratory center is excited, causing the person to breathe rapidly and deeply. This breathing increases the expiration of carbon dioxide and therefore removes it from the blood and the extracel- lular fluid until the concentration returns to normal. Normal Ranges of Important Extracellular Fluid Constituents Table 1–1 shows some important constituents of extra- cellular fluid along with their normal values, normal ranges, and maximum limits that can be endured for short periods without the occurrence of death. Note the narrowness of the ranges; levels outside these ranges are usually the cause or the result of illnesses. Characteristics of Control Systems Most Control Systems of the Body Operate by Negative Feedback. For regulation of carbon dioxide concentration, as discussed, a high concentration of carbon dioxide in the extracellular fluid increases pulmonary ventilation, which decreases carbon dioxide concentration, moving it toward normal levels. This mechanism is an example of negative feedback; that is, any stimulus that attempts to change the carbon dioxide concentration is counteracted by a response that is negative to the initiating stimulus.  Functional Organization of the Human Body and Control of the 7 “Internal Environment” Table 1–1 Some Important Constituents and Physical Characteristics of the Extracellular Fluid, Normal Range of Control, and Approximate VetBooks.ir Nonlethal Limits for Short Periods Average Approximate Normal Normal Nonlethal Parameter Units Values Ranges Limits Oxygen (venous) mm Hg 40 35–45 10–1000 Carbon dioxide mm Hg 45 40–50 5–80 (venous) Sodium ion mmol/L 142 138–146 115–175 Potassium ion mmol/L 4.2 3.8–5.0 1.5–9.0 Calcium ion mmol/L 1.2 1.0–1.4 0.5–2.0 Chloride ion mmol/L 106 103–112 70–130 Bicarbonate ion mmol/L 24 22–29 8–45 Glucose mg/dL 90 75–95 20–1500 Body ­temperature °F (°C) 98.4 98–98.8 65–110 (37.0) (37.0) (18.3–43.3) Acid-base pH 7.4 7.3–7.5 6.9–8.0 The degree of effectiveness with which a control system maintains constant conditions is determined by the gain of the negative feedback. The gain is calculated according to the following formula: Gain = Correction/Error Some control systems, such as those that regulate body temperature, have feedback gains as high as −33, which simply means that the degree of correction is 33 times greater than the remaining error. Feed-Forward Control Systems Anticipate Changes. Because of the many interconnections between control systems, the total control of a particular body function may be more complex than can be accounted for by simple negative feedback. For example, some movements of the body occur so rapidly that there is not sufficient time for nerve signals to travel from some of the peripheral body parts to the brain and then back to the periphery in time to control the movements. Therefore, the brain uses feed-forward control to cause the required muscle contractions. Sensory nerve signals from the moving parts inform the brain in retrospect of whether the appropriate movement, as envisaged by  8 UNIT I Introduction to Physiology: The Cell and General Physiology the brain, has been performed correctly. If it has not, the brain corrects the feed-forward signals it sends to the muscles the next time the movement is required. This VetBooks.ir process is also called adaptive control, which is, in a sense, delayed negative feedback. Positive Feedback Can Sometimes Cause Vicious Cycles and Death, and Other Times It Can Be Useful. A system that exhibits positive feedback responds to a perturbation with changes that amplify the perturbation and therefore leads to instability rather than stability. For example, severe hemorrhage may lower blood pressure to such a low level that blood flow to the heart is insufficient to maintain normal cardiac pumping; as a result, blood pressure falls even lower, further diminishing blood flow to the heart and causing still more weakness of the heart. Each cycle of this feedback leads to more of the same, which is a positive feedback or a vicious cycle. In some cases the body uses positive feedback to its advantage. An example is the generation of nerve sig- nals. When the nerve fiber membrane is stimulated, the slight leakage of sodium ions into the cell causes open- ing of more channels, more sodium entry, more change in membrane potential, and so forth. Therefore, a slight leak of sodium into the cell becomes an explosion of sodium entering the interior of the nerve fiber, which creates the nerve action potential. SUMMARY—AUTOMATICITY OF THE BODY (p. 10) The body is a social order of about 100 trillion cells orga- nized into various functional structures, the largest of which are called organs. Each functional structure, or organ, helps maintain a constant internal environ- ment. As long as homeostasis is maintained, the cells of the body continue to live and function properly. Thus, each cell benefits from homeostasis and, in turn, each cell contributes its share toward maintenance of homeostasis. This reciprocal interplay provides con- tinuous automaticity of the body until one or more functional systems lose their ability to contribute their share of function. When this loss happens, all the cells of the body suffer. Extreme dysfunction leads to death, whereas moderate dysfunction leads to sickness.  CHAPTER 2 The Cell and Its Functions VetBooks.ir ORGANIZATION OF THE CELL (p. 11) Figure 2–1 shows a typical cell, including the nucleus and cytoplasm, which are separated by the nuclear membrane. The cytoplasm is separated from interstitial fluid by a cell membrane that surrounds the cell. The substances that make up the cell are collectively called protoplasm, which is composed mainly of the following: Water constitutes 70 percent to 85 percent of most cells. Ions/electrolytes provide inorganic chemicals for cel- lular reactions. Some of the most important ions in the cell are potassium, magnesium, phosphate, sul- fate, bicarbonate, and small quantities of sodium, chloride, and calcium. Proteins normally constitute 10 to 20 percent of the cell mass. They can be divided into two types: struc- tural proteins and globular (functional) proteins, which are mainly enzymes. Lipids constitute about 2 percent of the total cell mass. Among the most important lipids in the cells are phospholipids, cholesterol, triglycerides, and neu- tral fats. In adipocytes (fat cells), triglycerides ac- count for as much as 95 percent of the cell mass and represent the body’s main energy storehouse. Carbohydrates play a major role in nutrition of the cell. Most human cells do not store large amounts of carbohydrates, which usually average about 1 percent of the total cell mass but may be as high as 3 percent in muscle cells and 6 percent in liver cells. The small amount of carbohydrates in the cells is usually stored in the form of glycogen, an insoluble polymer of glucose. PHYSICAL STRUCTURE OF THE CELL (p. 12) The cell (Figure 2–1) is not merely a bag of fluid and chemicals; it also contains highly organized physi- cal structures called organelles. Some of the principal organelles of the cell are the cell membrane, nuclear membrane, endoplasmic reticulum (ER), Golgi appara- tus, mitochondria, lysosomes, and centrioles. The Cell and Its Organelles Are Surrounded by Membranes Composed of Lipids and Proteins. The membranes that surround the cell and its organelles 9  10 UNIT I Introduction to Physiology: The Cell and General Physiology Chromosomes and DNA VetBooks.ir Centrioles Secretory granule Golgi apparatus Microtubules Nuclear Cell membrane membrane Cytoplasm Nucleolus Glycogen Ribosomes Lysosome Mitochondrion Granular Smooth Microfilaments endoplasmic (agranular) reticulum endoplasmic reticulum Figure 2–1 Reconstruction of a typical cell, showing the internal or- ganelles in the cytoplasm and nucleus. include the cell membrane, nuclear membrane, and membranes of the ER, mitochondria, lysosomes, and Golgi apparatus. They provide barriers that prevent free movement of water and water-soluble substances from one cell compartment to another. Proteins in the membrane often penetrate the membrane, providing pathways (channels) to allow movement of specific substances through the membranes. The Cell Membrane Is a Lipid Bilayer With Inserted Proteins. The lipid bilayer is composed almost entirely of phospholipids, sphingolipids, and cholesterol. Phos­ pholipids are the most abundant of the cell lipids and have a water-soluble (hydrophilic) portion and a portion that is soluble only in fats (hydrophobic). The hydrophobic portions of the phospholipids face each other, whereas the hydrophilic parts face the two surfaces of the membrane in contact with the surrounding interstitial fluid and the cell cytoplasm. This lipid bilayer membrane is highly permeable to lipid-soluble substances, such as oxygen, carbon diox- ide, and alcohol, but it acts as a major barrier to water- soluble substances, such as ions and glucose. Floating in the lipid bilayer are proteins, most of which are glyco- proteins (proteins combined with carbohydrates).  The Cell and Its Functions 11 There are two types of membrane protein: the inte- gral proteins, which protrude through the membrane, and the peripheral proteins, which are attached to the VetBooks.ir inner surface of the membrane and do not penetrate. Many of the integral proteins provide structural chan- nels (pores) through which water-soluble substances, especially ions, can diffuse. Other integral proteins act as carrier proteins for the transport of substances, sometimes against their gradients for diffusion. Integral proteins can also serve as receptors for sub- stances, such as peptide hormones, that do not easily penetrate the cell membrane. The peripheral proteins are normally attached to one of the integral proteins and usually function as enzymes that catalyze chemical reactions of the cell. The membrane carbohydrates occur mainly in com- bination with proteins and lipids in the form of glyco- proteins and glycolipids. The “glyco” portions of these molecules usually protrude to the outside of the cell. Many other carbohydrate compounds, called proteogly- cans, which are mainly carbohydrate substances bound together by small protein cores, are loosely attached to the outer surface; thus, the entire outer surface of the cell often has a loose carbohydrate coat called the glycocalyx. The carbohydrates on the outer surface of the cell have multiple functions: (1) they are often negatively charged and therefore repel other molecules that are negatively charged; (2) the glycocalyx of cells may attach to other cells (thus the cells attach to each other); (3) some of the carbohydrates act as receptors for binding hormones; and (4) some carbohydrate moieties enter into immune reactions, as discussed in Chapter 35. The Endoplasmic Reticulum Synthesizes Multiple Substances in the Cell. A large network of tubules and vesicles, called the endoplasmic reticulum (ER), penetrates almost all parts of the cytoplasm. The ER membrane provides an extensive surface area for the manufacture of many substances used inside the cells and released from some cells. They include proteins, carbohydrates, lipids, and other structures such as lysosomes, peroxisomes, and secretory granules. Lipids are made within the ER wall. For the synthesis of proteins, ribosomes attach to the outer surface of the granular ER. These ribosomes function in association with messenger RNA to synthesize many proteins that then enter the Golgi apparatus, where the molecules are further modified before they are released or used in the cell. Part of the ER has no attached ribosomes and is called the agranular, or smooth, ER. The agranular ER  12 UNIT I Introduction to Physiology: The Cell and General Physiology functions for the synthesis of lipid substances and for other processes of the cells promoted by intrareticular enzymes. VetBooks.ir The Golgi Apparatus Functions in Association With the ER. The Golgi apparatus has membranes similar to those of the agranular ER, is prominent in secretory cells, and is located on the side of the cell from which the secretory substances are extruded. Small transport vesicles, also called ER vesicles, continually pinch off from the ER and then fuse with the Golgi apparatus. In this way, substances entrapped in the ER vesicles are transported from the ER to the Golgi apparatus. The substances are then processed in the Golgi apparatus to form lysosomes, secretory vesicles, and other cytoplasmic components. Lysosomes Provide an Intracellular Digestive System. Lysosomes, which are found in great numbers in many cells, are small spherical vesicles surrounded by a membrane that contains digestive enzymes. These enzymes allow lysosomes to break down intracellular substances in structures, especially damaged cell structures, food particles that have been ingested by the cell, and unwanted materials such as bacteria. The membranes surrounding the lysosomes usually prevent the enclosed enzymes from coming in contact with other substances in the cell and therefore prevent their digestive action. When these membranes are dam- aged, the enzymes are released and split the organic substances with which they come in contact into highly diffusible substances such as amino acids and glucose. Mitochondria Release Energy in the Cell. An adequate supply of energy must be available to fuel the chemical reactions of the cell. This energy is provided mainly by the chemical reaction of oxygen with the three types of foods: glucose derived from carbohydrates, fatty acid derived from fats, and amino acids derived from proteins. After entering the cell, foods are split into smaller molecules that, in turn, enter the mitochondria, where other enzymes remove carbon dioxide and hydrogen ions in a process called the citric acid cycle. An oxidative enzyme system, which is also in the mitochondria, causes progressive oxidation of hydrogen atoms. The end products of mitochondria reactions are water and carbon dioxide. The energy liberated is used by mitochondria to synthesize another substance, adenosine triphosphate (ATP), a highly reactive chemical that can diffuse throughout the cell to release its energy whenever it is needed for the performance of cell functions.  The Cell and Its Functions 13 Mitochondria are also self-replicative, which means that one mitochondrion can form a second one, a third one, and so on whenever there is a need in the cell for VetBooks.ir increased amounts of ATP. There Are Many Cytoplasmic Structures and Organelles. Hundreds of types of cells are found in the body, and each has a special structure. Some cells, for example, are rigid and have large numbers of filamentous or tubular structures, which are composed of fibrillar proteins. A major function of these tubular structures is to act as a cytoskeleton, providing rigid physical structures for certain parts of cells. Some of the tubular structures, called microtubules, can transport substances from one area of the cell to another. One of the important functions of many cells is to secrete special substances, such as digestive enzymes. Almost all of the substances are formed by the ER- Golgi apparatus system and are released into the cyto- plasm inside storage vesicles called secretory vesicles. After a period of storage in the cell, they are expelled through the cell membrane to be used elsewhere in the body. The Nucleus Is the Control Center of the Cell and Contains Large Amounts of DNA, Also Called Genes (p. 17). Genes determine the characteristics of the proteins of the cell, including the enzymes of the cytoplasm. They also control reproduction. Genes first reproduce themselves through a process of mitosis in which two daughter cells are formed, each of which receives one of the two sets of genes. The nuclear membrane, also called the nuclear enve- lope, separates the nucleus from the cytoplasm. This structure is composed of two membranes; the outer membrane is continuous with the ER, and the space between the two nuclear membranes is also continuous with the compartment inside the ER. Both layers of the membrane are penetrated by several thousand nuclear pores, which are almost 100 nanometers in diameter. The nuclei in most cells contain one or more structures called nucleoli, which, unlike many of the organelles, do not have a surrounding membrane. The nucleoli contain large amounts of RNA and proteins of the type found in ribosomes. A nucleolus becomes enlarged when the cell is actively synthesizing proteins. Ribosomal RNA is stored in the nucleolus and trans- ported through the nuclear membrane pores to the cytoplasm, where it is used to produce mature ribo- somes, which play an important role in the formation of proteins.  14 UNIT I Introduction to Physiology: The Cell and General Physiology FUNCTIONAL SYSTEMS OF THE CELL (p. 19) Ingestion by the Cell—Endocytosis VetBooks.ir The cell obtains nutrients and other substances from the surrounding fluid through the cell membrane via diffusion and active transport. Very large particles enter the cell via endocytosis, the principal forms of which are pinocytosis and phagocytosis. Pinocytosis is the ingestion of small globules of ex- tracellular fluid, forming minute vesicles in the cell cytoplasm. This process is the only method by which large molecules, such as proteins, can enter the cells. These molecules usually attach to specialized recep- tors on the outer surface of the membrane that are concentrated in small pits called coated pits. On the inside of the cell membrane underneath these pits is a latticework of a fibrillar protein called clathrin and a contractile filament of actin and myosin. After the protein molecules bind with the receptors, the mem- brane invaginates and contractile proteins surround the pit, causing its borders to close over the attached proteins and form a pinocytotic vesicle. Phagocytosis is the ingestion of large particles, such as bacteria, cells, and portions of degenerating tissue. This ingestion occurs much in the same way as pino- cytosis except that it involves large particles instead of molecules. Only certain cells have the ability to perform phagocytosis, notably tissue macrophages and some white blood cells. Phagocytosis is initiated when proteins or large polysaccharides on the sur- face of the particle bind with receptors on the sur- face of the phagocyte. In the case of bacteria, these usually are attached to specific antibodies, and the antibodies in turn attach to the phagocyte receptors, dragging the bacteria along with them. This inter- mediation of antibodies is called opsonization and is discussed further in Chapters 34 and 35. Pinocytic and Phagocytic Foreign Substances Are Digested in the Cell by the Lysosomes. Almost as soon as pinocytic or phagocytic vesicles appear inside a cell, lysosomes become attached to the vesicles and empty their digestive enzymes into the vesicle. Thus, a digestive vesicle is formed in which the enzymes begin hydrolyzing the proteins, carbohydrates, lipids, and other substances in the vesicle. The products of digestion are small molecules of amino acids, glucose, phosphate, and so on that can diffuse through the membrane of the vesicle into the cytoplasm. The undigested substances, called the residual body, are excreted through the  The Cell and Its Functions 15 cell membrane via the process of exocytosis, which is basically the opposite of endocytosis. VetBooks.ir Synthesis of Cellular Structures by ER and Golgi Apparatus (p. 20) The Synthesis of Most Cell Structures Begins in the ER. Many of the products formed in the ER are then passed onto the Golgi apparatus, where they are further processed before release into the cytoplasm. The granular ER, characterized by large numbers of ribosomes attached to the outer surface, is the site of protein formation. Ribosomes synthesize the proteins and extrude many of them through the wall of the ER to the interior of the endoplasmic vesicles and tubules, called the endoplasmic matrix. When proteins enter the ER, enzymes in the ER wall cause rapid changes, including congregation of carbo- hydrates to form glycoproteins. In addition, the proteins are often cross-linked, folded, and shortened to form more compact molecules. The ER also synthesizes lipids, especially phospho- lipid and cholesterol, which are incorporated into the lipid bilayer of the ER. Small ER vesicles, or transport vesicles, continually break off from the smooth reticu- lum. Most of these vesicles migrate rapidly to the Golgi apparatus. The Golgi Apparatus Processes Substances Formed in the ER. As substances are formed in the ER, especially proteins, they are transported through the reticulum tubules toward the portions of the smooth ER that lie nearest the Golgi apparatus. Small transport vesicles, composed of small envelopes of smooth ER, continually break away and diffuse to the deepest layer of the Golgi apparatus. The transport vesicles instantly fuse with the Golgi apparatus and empty their contents into the vesicular spaces of the Golgi apparatus. Here, more carbohydrates are added to the secretions, and the ER secretions are compacted. As the secretions pass toward the outermost layers of the Golgi apparatus, the compaction and processing continue. Finally, small and large vesicles break away from the Golgi apparatus, carrying with them the compacted secretory substances. These substances can then diffuse throughout the cell. In a highly secretory cell, the vesicles formed by the Golgi apparatus are mainly secretory vesicles, which dif- fuse to the cell membrane, fuse with it, and eventually empty their substances to the exterior via a mechanism called exocytosis. Some of the vesicles made in the Golgi  16 UNIT I Introduction to Physiology: The Cell and General Physiology apparatus, however, are destined for intracellular use. For example, specialized portions of the Golgi appara- tus form lysosomes. VetBooks.ir Extraction of Energy From Nutrients by the Mitochondria (p. 22) The principal substances from which the cells extract energy are oxygen and one or more of the foodstuffs— carbohydrates, fats, and proteins—that react with oxy- gen. In humans, almost all carbohydrates are converted to glucose by the digestive tract and liver before they reach the cell; similarly, proteins are converted to amino acids, and fats are converted to fatty acids. Inside the cell, these substances react chemically with oxygen under the influence of enzymes that control the rates of reaction and channel the released energy in the proper direction. Oxidative Reactions Occur Inside the Mitochondria, and Energy Released Is Used to Form ATP. ATP is a nucleotide composed of the nitrogenous base adenine, the pentose sugar ribose, and three phosphate radicals. The last two phosphate radicals are connected with the remainder of the molecule by high-energy phosphate bonds, each of which contains about 12,000 calories of energy per mole of ATP under the usual conditions of the body. The high-energy phosphate bonds are labile so they can be split instantly whenever energy is required to promote other cellular reactions. When ATP releases its energy, a phosphoric acid radical is split away, and adenosine diphosphate (ADP) is formed. Energy derived from cell nutrients causes the ADP and phosphoric acid to recombine to form new ATP, with the entire process continuing over and over again. Most of the ATP Produced in the Cell Is Formed in Mitochondria. After entry into the cells, glucose is subjected to enzymes in the cytoplasm that convert it to pyruvic acid, a process called glycolysis. Less than 5 percent of the ATP formed in the cell occurs via glycolysis. Pyruvic acid derived from carbohydrates, fatty acids derived from lipids, and amino acids derived from proteins are all eventually converted to the compound acetyl–coenzyme A (acetyl-CoA) in the mitochondria matrix. This substance is then acted on by another series of enzymes in a sequence of chemical reactions called the citric acid cycle, or Krebs cycle. In the citric acid cycle, acetyl-CoA is split into hydro- gen ions and carbon dioxide. Hydrogen ions are highly  The Cell and Its Functions 17 reactive and eventually combine with oxygen that has diffused into the mitochondria. This reaction releases a tremendous amount of energy, which is used to convert VetBooks.ir large amounts of ADP to ATP. This requires large num- bers of protein enzymes that are integral parts of the mitochondria. The initial event in ATP formation is removal of an electron from the hydrogen atom, thereby converting it to a hydrogen ion. The terminal event is movement of the hydrogen ion through large globular proteins called ATP synthetase, which protrude through the mem- branes of the mitochondrial membranous shelves, which themselves protrude into the mitochondrial matrix. ATP synthetase is an enzyme that uses the energy and movement of the hydrogen ions to effect the conver- sion of ADP to ATP, and hydrogen ions combine with oxygen to form water. The newly formed ATP is trans- ported out of the mitochondria to all parts of the cell cytoplasm and nucleoplasm, where it is used to energize the functions of the cell. This overall process is called the chemosmotic mechanism of ATP formation. ATP Is Used for Many Cellular Functions. ATP promotes three types of cell function: (1) membrane transport, as occurs with the sodium-potassium pump, which transports sodium out of the cell and potassium into the cell; (2) synthesis of chemical compounds throughout the cell; and (3) mechanical work, as occurs with the contraction of muscle fibers or with ciliary and ameboid motion. Locomotion and Ciliary Movements of Cells (p. 24) The most obvious type of movement in the body is that of the specialized muscle cells in skeletal, cardiac, and smooth muscle, which constitute almost 50 percent of the entire body mass. Two other types of movement occur in other cells: ameboid locomotion and ciliary movement. Ameboid Movement of an Entire Cell in Relation to Its Surroundings. An example of ameboid locomotion is the movement of white blood cells through tissues. Typically, ameboid locomotion begins with protrusion of a pseudopodium from one end of the cell. This results from continual exocytosis, which forms a new cell membrane at the leading edge of the pseudopodium, and continual endocytosis of the membrane in the mid and rear portions of the cell. Two other effects are also essential to the forward movement of the cell. The first effect is attachment  18 UNIT I Introduction to Physiology: The Cell and General Physiology of the pseudopodium to the surrounding tissues so it becomes fixed in its leading position while the remain- der of the cell body is pulled forward toward the point VetBooks.ir of attachment. This attachment is effected by receptor proteins that line the insides of the exocytotic vesicles. The second requirement for locomotion is avail- able energy needed to pull the cell body in the direction of the pseudopodium. In the cytoplasm of all cells are molecules of the protein actin. When these molecules polymerize to form a filamentous network, the net- work contracts when it binds with another protein, for example, an actin-binding protein such as myosin. The entire process, which is energized by ATP, takes place in the pseudopodium of a moving cell, in which such a network of actin filaments forms inside the growing pseudopodium. The most important factor that usually initiates ame- boid movement is the process called chemotaxis, which results from the appearance of certain chemical sub- stances in the tissue called chemotactic substances. Ciliary Movement Is a Whiplike Movement of Cilia on the Surfaces of Cells. Ciliary movement occurs in only two places in the body: on the inside surfaces of the respiratory airways and on the inside surfaces of the uterine tubes (i.e., the fallopian tubes of the reproductive tract). In the nasal cavity and lower respiratory airways, the whiplike motion of the cilia causes a layer of mucus to move toward the pharynx at a rate of about 1 cm/min; in this way, passageways with mucus or particles that become entrapped in the mucus are continually cleared. In the uterine tubes, the cilia cause slow movement of fluid from the ostium of the uterine tube toward the uterine cavity; it is mainly this movement of fluid that transports the ovum from the ovary to the uterus. The mechanism of the ciliary movement is not fully understood, but at least two factors are necessary: (1) available ATP and (2) appropriate ionic conditions, including appropriate concentrations of magnesium and calcium.  CHAPTER 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction VetBooks.ir Genes in the Cell Nucleus Control Protein Synthesis (p. 27). The genes control protein synthesis in the cell and in this way control cell function. Proteins play a key role in almost all functions of the cell by serving as enzymes that catalyze the reactions of the cell and as major components of the physical structures of the cell. Each gene is a double-stranded, helical molecule of deoxyribonucleic acid (DNA) that controls formation of ribonucleic acid (RNA). The RNA, in turn, spreads throughout the cells to control the formation of a spe- cific protein. The entire process, from transcription of the genetic code in the nucleus to translation of the RNA code and formation of proteins in the cell cytoplasm, is often referred to as gene expression and is shown in ­Figure 3–1. Because there are about 30,000 genes in each cell, it is possible to form large numbers of different cel- lular proteins. In fact, RNA molecules transcribed from Plasma Nuclear membrane envelope Nucleus DNA Gene (DNA) DNA Transcription transcription RNA RNA formation RNA splicing Translation mRNA Ribosomes RNA transport Protein mRNA formation Translation of messenger RNA Cell Cell structure enzymes Protein Cytosol Cell function Figure 3–1 General schema by which the genes control cell function. 19  20 UNIT I Introduction to Physiology: The Cell and General Physiology the same gene can be processed in different ways by the cell, giving rise to alternate versions of the protein. The total number of different proteins produced by various VetBooks.ir cell types in humans is estimated to be at least 100,000. Nucleotides Are Organized to Form Two Strands of DNA Loosely Bound to Each Other. Genes are attached in an end- on-end manner in long, double-stranded, helical molecules of DNA that are composed of three basic building blocks: (1) phosphoric acid, (2) deoxyribose (a sugar), and (3) four nitrogenous bases: two purines (adenine and guanine) and two pyrimidines (thymine and cytosine). The first stage in DNA formation is the combina- tion of one molecule of phosphoric acid, one molecule of deoxyribose, and one of four bases to form a nucleo- tide. Four nucleotides can therefore be formed, one from each of the four bases. Multiple nucleotides are bound together to form two strands of DNA, and the two strands are loosely bound to each other. The backbone of each DNA strand is composed of alternating phosphoric acid and deoxyribose molecules. The purine and pyrimidine bases are attached to the side of the deoxyribose molecules, and loose bonds between the purine and pyrimidine bases of the two DNA strands hold them together. The purine base adenine of one strand always bonds with the pyrimidine base thymine of the other strand, whereas guanine always bonds with cytosine. The Genetic Code Consists of Triplets of Bases. Each group of three successive bases in the DNA strand is called a code word. These code words control the sequence of amino acids in the protein to be formed in the cytoplasm. One code word, for example, might be composed of a sequence of adenine, thymine, and guanine, whereas the next code word might have a sequence of cytosine, guanine, and thymine. These two code words have entirely different meanings because their bases are different. The sequence of successive code words of the DNA strand is known as the genetic code. THE DNA CODE IN THE NUCLEUS IS TRANSFERRED TO RNA CODE IN THE CELL CYTOPLASM—THE PROCESS OF TRANSCRIPTION (p. 30) Because DNA is located in the nucleus and many func- tions of the cell are carried out in the cytoplasm, there must be some method by which the genes of the nucleus control the chemical reactions of the cytoplasm. This is achieved through RNA, the formation of which is con- trolled by DNA. During this process the code of DNA is transferred to RNA, a process called transcription.  Genetic Control of Protein Synthesis, Cell Function, and Cell 21 Reproduction The RNA diffuses from the nucleus to the nuclear pores into the cytoplasm, where it controls protein synthesis. RNA Is Synthesized in the Nucleus From a DNA Template. VetBooks.ir During synthesis of RNA, the two strands of the DNA molecule separate, and one of the two strands is used as a template for RNA synthesis. The code triplets in DNA cause the formation of complementary code triplets (called codons) in RNA; these codons then control the sequence of amino acids in a protein to be synthesized later in the cytoplasm. Each DNA strand in each chromosome carries the code for perhaps as many as 2000 to 4000 genes. The basic building blocks of RNA are almost the same as those of DNA except that in RNA, the sugar ribose replaces the sugar deoxyribose and the pyrimi- dine uracil replaces thymine. The basic building blocks of RNA combine to form four nucleotides, exactly as described for the synthesis of DNA. These nucleotides contain the bases adenine, guanine, cytosine, and uracil. The next step in the RNA synthesis is activation of the nucleotides, which occurs through the addition of two phosphate radicals to each nucleotide to form tri- phosphates. These last two phosphates are combined with the nucleotide by high-energy phosphate bonds, which are derived from the adenosine triphosphate (ATP) of the cell. This activation process makes avail- able large quantities of energy, which is used for pro- moting the chemical reactions that add each new RNA nucleotide to the end of the RNA chain. The DNA Strand Is Used as a Template to Assemble the RNA Molecule From Activated Nucleotides. The assembly of the RNA molecule occurs under the influence of the enzyme RNA polymerase as follows: 1. In the DNA strand immediately ahead of the gene that is to be transcribed is a sequence of nucleotides called the promoter. An RNA polymerase recognizes this promoter and attaches to it. 2. The polymerase causes unwinding of two turns of the DNA helix and separation of the unwound portions. 3. The polymerase moves along the DNA strand and begins forming the RNA molecules by binding com- plementary RNA nucleotides to the DNA strand. 4. The successive RNA nucleotides then bind to each other to form an RNA strand. 5. When the RNA polymerase reaches the end of the DNA gene, it encounters a sequence of DNA mole­ cules called the chain-terminating sequence, caus- ing the polymerase to break away from the DNA strand. The RNA strand is then released into the nucleoplasm.  22 UNIT I Introduction to Physiology: The Cell and General Physiology The code present in the DNA strand is transmitted in complementary form to the RNA molecule as fol- lows: VetBooks.ir DNA Base RNA Base Guanine Cytosine Cytosine Guanine Adenine Uracil Thymine Adenine There Are Several Types of RNA. Research on RNA has uncovered many different types of RNA. Some are involved in protein synthesis, whereas others serve gene regulatory functions or are involved in posttranscriptional modification of RNA. The following six types of RNA play independent and different roles in protein synthesis: 1.  Precursor messenger RNA (pre-mRNA), a large, im- mature single strand of RNA that is processed in the nucleus to form mature mRNA and includes two different types of segments called introns, which are removed by a process called splicing, and exons, which are retained in the final mRNA 2. Small nuclear RNA (snRNA), which directs the splicing of pre-mRNA to form mRNA 3. mRNA, which carries the genetic code to the cyto- plasm to control the formation of proteins 4. ribosomal RNA, which, along with proteins, forms the ribosomes, the structures in which protein mol- ecules are assembled 5. Transfer RNA (tRNA), which transports activated amino acids to the ribosomes to be used in the as- sembly of the proteins 6. microRNA (miRNA), which are single-stranded RNA molecules of 21 to 23 nucleotides that can regulate gene transcription and translation There are 20 types of tRNA, each of which combines specifically with one of the 20 amino acids and carries this amino acid to the ribosomes, where it is incorporated in the protein molecule. The code in the tRNA that allows it to recognize a specific codon is a triplet of nucleotide bases called an anticodon. During formation of the pro- tein molecule, the three anticodon bases combine loosely by hydrogen bonding with the codon bases of the mRNA. In this way, the various amino acids are lined up along the mRNA chain, thus establishing the proper sequence of amino acids in the protein molecule.  Genetic Control of Protein Synthesis, Cell Function, and Cell 23 Reproduction TRANSLATION—SYNTHESIS OF POLYPEPTIDES ON RIBOSOMES FROM GENETIC CODE IN mRNA (p. 33) VetBooks.ir To manufacture proteins, one end of the mRNA strand enters the ribosome, and then the entire strand threads its way through the ribosome in just over a minute. As it passes through, the ribosome “reads” the genetic code and causes the proper succession of amino acids to bind together to form chemical bonds called peptide linkages. The mRNA does not recognize the different types of amino acids but, instead, recognizes the different types of tRNA. Each type of tRNA molecule carries only one specific type of amino acid that is incorporated into the protein. Thus, as the strand of mRNA passes through the ribo- some, each of its codons attracts to it a specific tRNA that, in turn, delivers a specific amino acid. This amino acid then combines with the preceding amino acids to form a peptide linkage, and this sequence continues to build until an entire protein molecule is formed. At this point, a chain-terminating (or “stop”) codon appears and indicates completion of the process, and the protein is released into the cytoplasm or through the membrane of the endoplasmic reticulum to the interior. CONTROL OF GENE FUNCTION AND BIOCHEMICAL ACTIVITY IN CELLS (p. 35) The genes control the function of each cell by determin- ing the relative proportion of various types of enzymes and structural proteins that are formed. Regulation of gene expression covers the entire process from tran- scription of the genetic code in the nucleus to the for- mation of proteins in the cytoplasm. The Promoter Controls Gene Expression. Cellular protein synthesis starts with transcription of DNA into RNA, a process controlled by regulatory elements in the promoter of a gene. In eukaryotes, including mammals, the basal promoter consists of a sequence of seven bases (TATAAAA) called the TATA box, which is the binding site for the TATA-binding protein and several other important transcription factors that are collectively referred to as the transcription factor IID complex. In addition to the transcription factor IID complex, this region is where transcription factor IIB binds to both the DNA and RNA polymerase 2 to facilitate transcription of the DNA into RNA. This basal promoter is found in all protein coding genes,  24 UNIT I Introduction to Physiology: The Cell and General Physiology and the polymerase must bind with this basal promoter before it can begin traveling along the DNA strand to synthesize RNA. The upstream promoter is located VetBooks.ir further upstream from the transcription start site and contains several binding sites for positive or negative transcription factors that can effect transcription through interactions with proteins bound to the basal promoter. The structure and transcription factor binding sites in the upstream promoter vary from gene to gene to give rise to the different expression patterns of genes in different tissues. Transcription of genes in eukaryotes is also influ- enced by enhancers, which are regions of DNA that can bind transcription factors. Enhancers can be located far from the gene they act on or even on a different chro- mosome. Although enhancers may be located a great distance away from their target gene, they may be rela- tively close when DNA is coiled in the nucleus. It is esti- mated that there are 110,000 gene enhancer sequences in the human genome. Control of the Promoter Through Negative Feedback by the Cell Product. When the cell produces a critical amount of substance, it causes negative feedback inhibition of the promoter that is responsible for its synthesis. This inhibition can be accomplished by causing a regulatory repressor protein to bind at the repressor operator or a regulatory activator protein to break this bond. In either case, the promoter becomes inhibited. Other mechanisms are available for control of tran- scription by the promoter, including the following: 1. A promoter may be controlled by transcription fac- tors located elsewhere in the genome. 2. In some instances, the same regulatory protein func- tions as an activator for one promoter and as a re- pressor for another, allowing different promoters to be controlled at the same time by the same regula- tory protein. 3. The nuclear DNA is packaged in specific structural units, the chromosomes. Within each chromosome, the DNA is wound around small proteins called his- tones, which are held together tightly in a compacted state with other proteins. As long as DNA is in this compacted state, it cannot function to form RNA. Multiple mechanisms exist, however, that can cause selected areas of the chromosomes to become de- compacted, allowing RNA transcription. Even then, specific transcription factors control the actual rate of transcription by the promoter in the chromo- some.  Genetic Control of Protein Synthesis, Cell Function, and Cell 25 Reproduction THE DNA–GENETIC SYSTEM CONTROLS CELL REPRODUCTION (p. 37) VetBooks.ir The genes and their regulatory mechanisms determine not only the growth characteristics of cells but also when and whether these cells divide to form new cells. In this way, the genetic system controls each stage of the development of the human from the single-cell fertil- ized ovum to the whole functioning body. Most cells of the body, with the exception of mature red blood cells, striated muscle cells, and neurons, are capable of reproducing other cells of their own type. Ordinarily, as sufficient nutrients are available, each cell increases in size until it divides via mitosis to form two new cells. Different cells of the body have different life cycle periods that vary from as short as 10 hours for highly stimulated bone marrow cells to the entire life- time of the human body for nerve cells. Cell Reproduction Begins With Replication of DNA. Mitosis can take place only after all of the DNA in the chromosomes has been replicated. The DNA is duplicated only once, so the net result is two exact replicates of all DNA. These replicates then become the DNA of the two daughter cells that will be formed at mitosis. The replication of DNA is similar to the way RNA is transcribed from DNA, except for a few important differences: 1. Both strands of the DNA are replicated, not just one of them. 2. Both strands of the DNA helix are replicated from end to end rather than small portions of them, as oc- curs during the transcription of RNA by genes. 3. The principal enzymes for replication of DNA are a complex of several enzymes called DNA polymerase, which is comparable to RNA polymerase. 4. Each newly formed DNA strand remains attached by loose hydrogen bonding to the original DNA strand that is used as its template. Two DNA helixes that are formed, therefore, are duplicates of each other and are still coiled together. 5. The two new helixes become uncoiled by the action of enzymes that periodically cut each helix along its entire length, rotate each segment sufficiently to cause separation, and then resplice the helix. DNA Strands Are “Repaired” and “Proofread.” During the time between the replication of DNA and the beginning of mitosis, there is a period of “proofreading” and “repair” of the DNA strands. Whenever inappropriate DNA nucleotides have been matched up with the nucleotides  26 UNIT I Introduction to Physiology: The Cell and General Physiology of the original template strand, special enzymes cut out the defective areas and replace them with the appropriate complementary nucleotides. Because of VetBooks.ir proofreading and repair, the transcription process rarely makes a mistake. When a mistake is made, however, it is called a mutation. Entire Chromosomes Are Replicated. The DNA helixes of the nucleus are