Pocket Companion to Guyton and Hall Textbook of Medical Physiology PDF

 Pocket Companion to Guyton and Hall Textbook of Medical Physiology This page intentionally left blank  TWELFTH EDITION Pocket Companion to Guyton and Hall Textbook of Medical Physiology John E. Hall PhD...

 Pocket Companion to Guyton and Hall Textbook of Medical Physiology This page intentionally left blank  TWELFTH EDITION Pocket Companion to Guyton and Hall Textbook of Medical Physiology John E. Hall PhD Arthur C. Guyton Professor and Chair Department of Physiology and Biophysics Associate Vice Chancellor for Research University of Mississippi Medical Center Jackson, Mississippi  1600 John F. Kennedy Blvd. Ste. 1800 Philadelphia, PA 19103-2899 POCKET COMPANION TO GUYTON AND HALL ISBN: 978-1-4160-5451-1 TEXTBOOK OF MEDICAL PHYSIOLOGY, TWELFTH EDITION Copyright # 2012, 2006, 2001, 1998 by Saunders, Inc., an imprint of Elsevier Inc. All rights reserved. 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 Publisher'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 copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, 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 administration, 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, contributors, or editors, assume any liability for any injury and/or damage to persons 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. Illustrations by Michael Schenk and Walter Cunningham International Standard Book Number 978-1-4160-5451-1 Executive Editor: William Schmitt Senior Project Manager: Claire Kramer Managing Editor: Rebecca Gruliow Designer: Louis Forgione Publishing Services Manager: Patricia Tannian 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 Professor of Physiology and Biophysics University of Mississippi Medical Center Jackson, Mississippi Membrane Physiology, Nerve, and Muscle (Chapters 4–8) Respiration (Chapters 37–42) Aviation, Space, and Deep-Sea Diving Physiology (Chapters 43–44) Gastrointestinal Physiology (Chapters 62–66) David J. Dzielak, PhD Professor of Surgery Professor of Health Sciences Associate Professor of Physiology and Biophysics University of Mississippi Medical Center Jackson, Mississippi Blood Cells, Immunity, and Blood Coagulation (Chapters 32–36) The Nervous System: A. General Principles and Sensory Physiology (Chapters 45–48) The Nervous System: B. The Special Senses (Chapters 49–53) The Nervous System: C. Motor and Integrative Neurophysiology (Chapters 54–59) John E. Hall, PhD Arthur C. Guyton Professor and Chair Department of Physiology and Biophysics Associate Vice Chancellor for 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 25–31) The Nervous System: C. Motor and Integrative Neurophysiology (Chapters 60–61) v vi Contributors Metabolism and Temperature Regulation (Chapters 67–73) Endocrinology and Reproduction (Chapters 79–83) Thomas E. Lohmeier, PhD Professor of Physiology and Biophysics University of Mississippi Medical Center Jackson, Mississippi Endocrinology and Reproduction (Chapters 74–78) R. Davis Manning, PhD Professor of Physiology and Biophysics University of Mississippi Medical Center Jackson, Mississippi The Heart (Chapters 9–13) The Circulation (Chapters 20–24) Sports Physiology (Chapter 84)  Preface Human physiology is the discipline that links basic sciences with clinical medicine. It is integrative and encompasses everything from the study of molecules and subcellular components to the study of organ sys- tems and their interactions that allow us to function as living beings. Because human physiology is a rapidly expanding discipline and covers a broad scope, the vast amount of information potentially applicable to the practice of medicine can be overwhelming. Therefore, one of our 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 the basic physio- logic principles necessary for the study of medicine. The pocket companion was designed to accompany Guyton and Hall's Textbook of Medical Physiology, 12th Edition, and it cannot serve as a substitute for the par- ent text. Rather, it is intended to serve as a concise overview of the most important facts and concepts from the parent text, presented in a manner that facil- itates rapid comprehension of basic physiologic princi- ples. Some of the most important features of the pocket companion are as follows: It has been 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. The size of the book has been restricted so it can fit conveniently in a coat pocket as an immediate source of information when needed. Although the pocket companion contains the most important facts necessary for studying physiology, it vii viii Preface does not contain the details that enrich the physiologic concepts or the clinical examples of abnormal physiol- ogy that are contained in the parent book. We there- fore recommend that the pocket companion be used in conjunction with the Textbook of Medical Physiology, 12th Edition. 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 ability to present information effectively to students. 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 Introduction to Physiology: The Cell and General Physiology CHAPTER 1 Functional Organization of the Human Body and Control of the “Internal Environment” 3 CHAPTER 2 The Cell and Its Functions 10 CHAPTER 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction 20 UNIT II Membrane Physiology, Nerve, and Muscle CHAPTER 4 Transport of Substances through Cell Membranes 31 CHAPTER 5 Membrane Potentials and Action Potentials 38 CHAPTER 6 Contraction of Skeletal Muscle 45 CHAPTER 7 Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling 53 CHAPTER 8 Excitation and Contraction of Smooth Muscle 57 ix x Contents UNIT III The Heart CHAPTER 9 Cardiac Muscle; The Heart as a Pump and Function of the Heart Valves 65 CHAPTER 10 Rhythmical Excitation of the Heart 73 CHAPTER 11 The Normal Electrocardiogram 78 CHAPTER 12 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis 81 CHAPTER 13 Cardiac Arrhythmias and Their Electrocardiographic Interpretation 86 UNIT IV The Circulation CHAPTER 14 Overview of the Circulation; Biophysics of Pressure, Flow, and Resistance 93 CHAPTER 15 Vascular Distensibility and Functions of the Arterial and Venous Systems 99 CHAPTER 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow 106 CHAPTER 17 Local and Humoral Control of Tissue Blood Flow 116 CHAPTER 18 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure 124  Contents xi CHAPTER 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension: The Integrated System for Arterial Pressure Regulation 133 CHAPTER 20 Cardiac Output, Venous Return, and Their Regulation 145 CHAPTER 21 Muscle Blood Flow and Cardiac Output During Exercise; the Coronary Circulation and Ischemic Heart Disease 152 CHAPTER 22 Cardiac Failure 159 CHAPTER 23 Heart Valves and Heart Sounds; Valvular and Congenital Heart Defects 165 CHAPTER 24 Circulatory Shock and Its Treatment 171 UNIT V The Body Fluids and Kidneys CHAPTER 25 The Body Fluid Compartments: Extracellular and Intracellular Fluids; Edema 181 CHAPTER 26 Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control 191 CHAPTER 27 Urine Formation by the Kidneys: II. Tubular Reabsorption and Secretion 201 CHAPTER 28 Urine Concentration and Dilution; Regulation of Extracellular Fluid Osmolarity and Sodium Concentration 214 xii Contents CHAPTER 29 Renal Regulation of Potassium, Calcium, Phosphate, and Magnesium; Integration of Renal Mechanisms for Control of Blood Volume and Extracellular Fluid Volume 223 CHAPTER 30 Acid-Base Regulation 236 CHAPTER 31 Diuretics, Kidney Diseases 248 UNIT VI Blood Cells, Immunity, and Blood Coagulation CHAPTER 32 Red Blood Cells, Anemia, and Polycythemia 259 CHAPTER 33 Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System, and Inflammation 265 CHAPTER 34 Resistance of the Body to Infection: II. Immunity and Allergy Innate Immunity 271 CHAPTER 35 Blood Types; Transfusion; Tissue and Organ Transplantation 279 CHAPTER 36 Hemostasis and Blood Coagulation 282 UNIT VII Respiration CHAPTER 37 Pulmonary Ventilation 291 CHAPTER 38 Pulmonary Circulation, Pulmonary Edema, Pleural Fluid 298  Contents xiii CHAPTER 39 Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide through the Respiratory Membrane 305 CHAPTER 40 Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids 314 CHAPTER 41 Regulation of Respiration 320 CHAPTER 42 Respiratory Insufficiency—Pathophysiology, Diagnosis, Oxygen Therapy 324 UNIT VIII Aviation, Space, and Deep-Sea Diving Physiology CHAPTER 43 Aviation, High-Altitude, and Space Physiology 333 CHAPTER 44 Physiology of Deep-Sea Diving and Other Hyperbaric Conditions 338 UNIT IX The Nervous System: A. General Principles and Sensory Physiology CHAPTER 45 Organization of the Nervous System, Basic Functions of Synapses, and Neurotransmitters 345 CHAPTER 46 Sensory Receptors, Neuronal Circuits for Processing Information 353 CHAPTER 47 Somatic Sensations: I. General Organization, the Tactile and Position Senses 359 xiv Contents CHAPTER 48 Somatic Sensations: II. Pain, Headache, and Thermal Sensations 366 UNIT X The Nervous System: B. The Special Senses CHAPTER 49 The Eye: I. Optics of Vision 377 CHAPTER 50 The Eye: II. Receptor and Neural Function of the Retina 382 CHAPTER 51 The Eye: III. Central Neurophysiology of Vision 392 CHAPTER 52 The Sense of Hearing 398 CHAPTER 53 The Chemical Senses—Taste and Smell 404 UNIT XI The Nervous System: C. Motor and Integrative Neurophysiology CHAPTER 54 Motor Functions of the Spinal Cord; the Cord Reflexes 411 CHAPTER 55 Cortical and Brain Stem Control of Motor Function 418 CHAPTER 56 Contributions of the Cerebellum and Basal Ganglia to Overall Motor Control 427 CHAPTER 57 Cerebral Cortex, Intellectual Functions of the Brain, Learning, and Memory 439  Contents xv CHAPTER 58 Behavioral and Motivational Mechanisms of the Brain—The Limbic System and the Hypothalamus 447 CHAPTER 59 States of Brain Activity—Sleep, Brain Waves, Epilepsy, Psychoses 453 CHAPTER 60 The Autonomic Nervous System and the Adrenal Medulla 458 CHAPTER 61 Cerebral Blood Flow, Cerebrospinal Fluid, and Brain Metabolism 468 UNIT XII Gastrointestinal Physiology CHAPTER 62 General Principles of Gastrointestinal Function—Motility, Nervous Control, and Blood Circulation 477 CHAPTER 63 Propulsion and Mixing of Food in the Alimentary Tract 484 CHAPTER 64 Secretory Functions of the Alimentary Tract 489 CHAPTER 65 Digestion and Absorption in the Gastrointestinal Tract 496 CHAPTER 66 Physiology of Gastrointestinal Disorders 502 UNIT XIII Metabolism and Temperature Regulation CHAPTER 67 Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate 509 xvi Contents CHAPTER 68 Lipid Metabolism 516 CHAPTER 69 Protein Metabolism 525 CHAPTER 70 The Liver as an Organ 529 CHAPTER 71 Dietary Balances; Regulation of Feeding; Obesity and Starvation; Vitamins and Minerals 534 CHAPTER 72 Energetics and Metabolic Rate 546 CHAPTER 73 Body Temperature Regulation, and Fever 549 UNIT XIV Endocrinology and Reproduction CHAPTER 74 Introduction to Endocrinology 557 CHAPTER 75 Pituitary Hormones and Their Control by the Hypothalamus 563 CHAPTER 76 Thyroid Metabolic Hormones 573 CHAPTER 77 Adrenocortical Hormones 581 CHAPTER 78 Insulin, Glucagon, and Diabetes Mellitus 591 CHAPTER 79 Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth 600 CHAPTER 80 Reproductive and Hormonal Functions of the Male (and Function of the Pineal Gland) 608  Contents xvii CHAPTER 81 Female Physiology Before Pregnancy and Female Hormones 613 CHAPTER 82 Pregnancy and Lactation 622 CHAPTER 83 Fetal and Neonatal Physiology 630 UNIT XV Sports Physiology CHAPTER 84 Sports Physiology 637 Index 645 This page intentionally left blank  I Introduction to Physiology: The Cell and General Physiology 1. Functional Organization of the Human Body and Control of the “Internal Environment” 2. The Cell and Its Functions 3. Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction This page intentionally left blank  CHAPTER 1 Functional Organization of the Human Body and Control of the “Internal Environment” The goal of physiology is 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 includes the functions of molecules and subcellular components; tissues; organs; organ systems, such as the cardiovascular system; and the interaction and communication among these components. A distinguishing feature of physiol- ogy 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, tis- sues, 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 75 to 100 trillion cells, each of which is adapted to per- form 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 normal function of the cells; (2) most cells have the ability 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. “Homeostatic” Mechanisms of the Major Functional Systems (p. 4) Essentially all of the organs and tissues of the body per- form functions that help maintain the constituents of the extracellular fluid relatively constant, a condition 3 4 UNIT I Introduction to Physiology: The Cell and General Physiology called homeostasis. Much of our discussion of physiol- ogy focuses on the 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 around the circulatory system, and the second stage is movement of fluid between the blood capillaries and cells. The circulatory system keeps the fluids 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 dif- fuses back and forth into the interstitial fluid that lies between the cells, allowing continuous 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 absorbs various nutrients, including carbohydrates, fatty acids, and amino acids, into the extracellular fluid. The liver changes the chemical composition of many of the absorbed substances to more usable forms, and other tissues of the body (e.g., fat cells, kidneys, endo- crine 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 provides protection of internal organs and support of the body. Removal of Metabolic End Products (p. 5) The respiratory system not only provides oxygen to 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 external environment. The kidneys excrete most of the waste products other than carbon dioxide. The kidneys play a major role in regulating the extracellular fluid composition by controlling the excretion of salts, water, and waste  Functional Organization of the Human Body and Control 5 of the “Internal Environment” 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 produced in the body as well as toxic substances that are ingested. Regulation of Body Functions The nervous system directs the activity of the muscu- lar system, thereby providing locomotion. It also con- trols the function of many internal organs through the autonomic nervous system, and it allows us to sense our external and internal environment and to be intelligent beings so we can obtain the most advantageous conditions for survival. The hormone systems control many of the metabolic functions of the cells, such as growth, rate of metab- olism, and special activities associated with reproduc- tion. Hormones are secreted into the bloodstream and are carried to tissues throughout the body to help regulate 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 pro- tection of underlying tissues against dehydration. The skin also serves to regulate body temperature. Reproduction The reproductive system provides for formation of new beings like ourselves. Even this can be considered 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 as well as extracellular functions. Other control systems 6 UNIT I Introduction to Physiology: The Cell and General Physiology operate within the organs or throughout the entire body to control interactions among the organs. Regulation of oxygen and carbon dioxide concentra- tions in the extracellular fluid is a good example of mul- tiple control systems that operate together. In this instance, the respiratory system operates in association with the nervous system. When the carbon dioxide concentration in the blood increases above normal, the respiratory center is excited, causing the person to breathe rapidly and deeply. This increases the expira- tion of carbon dioxide and therefore removes it from the blood and the extracellular fluid until the concen- tration returns to normal. Normal Ranges of Important Extracellular Fluid Constituents Table 1–1 shows some of the important constituents of extracellular fluid along with their normal values, normal ranges, and maximum limits that can be endured for short periods of time 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 concentra- tion as discussed, a high concentration of carbon dioxide in the extracellular fluid increases pulmonary ventilation, which decreases the carbon dioxide concentration toward normal levels. This is an example of negative feed- back; any stimulus that attempts to change the carbon dioxide concentration is counteracted by a response that is negative to the initiating stimulus. The degree of effectiveness with which a control system maintains constant conditions is determined by the gain of the negative feedback. The gain is calcu- lated according to the following formula. Gain ¼ 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 Table 1–1. Some Important Constituents and Physical Characteristics of the Extracellular Fluid, Normal Range of Control, and Approximate Nonlethal Limits for Short Periods Functional Organization of the Human Body and Control Parameter Units Average Normal Values Normal Ranges Approximate Nonlethal Limits Oxygen mm Hg 40 35–45 10–1000 Carbon dioxide mm Hg 40 35–45 5–80 Sodium ion mmol/L 142 138–146 115–175 Potassium ion mmol/L 4.2 3.8–5.0 1.5–9.0 of the “Internal Environment” Calcium ion mmol/L 1.2 1.0–1.4 0.5–2.0 Chloride ion mmol/L 108 103–112 70–130 Bicarbonate ion mmol/L 28 24–32 8–45 Glucose mg/dL 85 75–95 20–1500  Body temperature F ( C) 98.4 (37.0) 98–98.8 (37.0) 65–110 (18.3–43.3) Acid-base pH 7.4 7.3–7.5 6.9–8.0 7 8 UNIT I Introduction to Physiology: The Cell and General Physiology simple negative feedback. For example, some move- ments of the body occur so rapidly that there is not suf- ficient 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 apprise the brain in retrospect of whether the appropriate movement, as envisaged by 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 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 Can Be Useful. A system that exhibits positive feedback responds to a perturbation with changes that amplify the perturba- tion and therefore leads to instability rather than stabil- ity. 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 dimin- ishing 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 opening 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 explo- sion of sodium entering the interior of the nerve fiber, which creates the nerve action potential. Summary—Automaticity of the Body (p. 9) The body is a social order of about 75 to 100 trillion cells organized into various functional structures, the largest of which are called organs. Each functional structure, or organ, has a role in maintaining a constant internal environment. So long as homeostasis is main- tained, the cells of the body continue to live and function properly. Thus, each cell benefits from  Functional Organization of the Human Body and Control 9 of the “Internal Environment” homeostasis and, in turn, each cell contributes its share toward the maintenance of homeostasis. This recipro- cal interplay provides continuous automaticity of the body until one or more functional systems lose their ability to contribute their share of function. When this loss happens, all cells of the body suffer. Extreme dys- function leads to death, whereas moderate dysfunction leads to sickness. CHAPTER 2 The Cell and Its Functions Organization of the Cell (p. 11) Figure 2–1 shows a typical cell, including the nucleus and cytoplasm, which are separated by the nuclear mem- brane. The cytoplasm is separated from interstitial fluid, which surrounds the cell, by a cell membrane. The sub- stances that make up the cell are collectively called pro- toplasm, which is composed mainly of the following. Water comprises 70% to 85% of most cells. Electrolytes provide inorganic chemicals for cellular reactions. Some of the most important electrolytes in the cell are potassium, magnesium, phosphate, sul- fate, bicarbonate, and small quantities of sodium, chloride, and calcium. Proteins normally constitute 10% to 20% of the cell mass. They can be divided into two types: structural proteins and globular (functional) proteins (which are mainly enzymes). Lipids constitute about 2% of the total cell mass. Among the most important lipids in the cells are phospholipids, cholesterol, triglycerides, and neutral fats. In adipocytes (fat cells), triglycerides may account for as much as 95% of the cell mass. 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% of the total cell mass but may be as high as 3% in mus- cle cells and 6% 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 (Fig. 2–1) is not merely a bag of fluid and che- micals; it also contains highly organized physical struc- tures called organelles. Some of the principal organelles of the cell are the cell membrane, nuclear membrane, endoplasmic reticulum (ER), Golgi apparatus, mito- chondria, lysosomes, and centrioles. The Cell and Its Organelles Are Surrounded by Membranes Composed of Lipids and Proteins. These membranes include the cell membrane, nuclear mem- brane, and membranes of the ER, mitochondria, lyso- somes, and Golgi apparatus. They provide barriers that prevent free movement of water and water-soluble sub- stances from one cell compartment to another. Protein 10  The Cell and 11 Its Functions Chromosomes and DNA 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 organelles of the cytoplasm and nucleus. molecules in the membrane often penetrate the mem- brane, 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 and cholesterol. Phospholipids have a water-soluble portion (hydrophilic) 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 mem- brane 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 dioxide, 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). There are two types of membrane protein: the inte- gral proteins, which protrude through the membrane, 11 12 UNIT I Introduction to Physiology: The Cell and General Physiology and the peripheral proteins, which are attached to the 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 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 hor- mones; and (4) some carbohydrate moieties enter into immune reactions, as discussed in Chapter 34. The ER Synthesizes Multiple Substances in the Cell. A large network of tubules and vesicles, called the ER, penetrates almost all parts of the cytoplasm. The mem- brane of the ER provides an extensive surface area for the manufacture of many substances used inside the cells and released from some cells. They include pro- teins; carbohydrates; lipids; and other structures such as lysosomes, peroxisomes, and secretory granules. Lipids are made within the ER wall. For the synthe- sis of proteins, ribosomes attach to the outer surface of the granular ER. These function in association with messenger RNA to synthesize many proteins that then enter the Golgi apparatus, where the molecules are fur- ther 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  The Cell and 13 Its Functions functions for the synthesis of lipid substances and for other processes of the cells promoted by intrareticular enzymes. 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 appara- tus to form lysosomes, secretory vesicles, and other cytoplasmic components. Lysosomes Provide an Intracellular Digestive System. Lysosomes, 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 par- ticles 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 damaged, however, the enzymes are released and split the organic substances with which they come in con- tact into highly diffusible substances such as amino acids and glucose. Mitochondria Release Energy in the Cell. An ade- quate supply of energy must be available to fuel the chemical reactions of the cell. This 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 acid derived from pro- teins. After entering the cell, the 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 mito- chondria, causes progressive oxidation of the hydrogen atoms. The end products of the reactions of the mito- chondria are water and carbon dioxide. The energy liberated is used by the mitochondria to synthesize another substance, adenosine triphosphate (ATP), 14 UNIT I Introduction to Physiology: The Cell and General Physiology which is a highly reactive chemical that can diffuse throughout the cell to release its energy whenever it is needed for the performance of cell functions. 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 increased amounts of ATP. There Are Many Cytoplasmic Structures and Orga- nelles. There are hundreds of types of cells in the body, and each has a special structure. Some cells, for exam- ple, are rigid and have large numbers of filamentous or tubular structures, which are composed of fibrillar pro- teins. 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 cytoplasm 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). The genes determine the characteristics of the proteins of the cell, including the enzymes of the cytoplasm. They also control reproduction. They 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 struc- tures called nucleoli, which unlike many of the organelles do not have a surrounding membrane. The nucleoli con- tain 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 transported through the  The Cell and 15 Its Functions nuclear membrane pores to the cytoplasm, where it is used to produce mature ribosomes, which play an important role in the formation of proteins. Functional Systems of the Cell (p. 18) Ingestion by the Cell—Endocytosis 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 extra- cellular fluid, forming minute vesicles in the cell cyto- plasm. This 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 membrane invaginates and contractile proteins sur- round 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 pinocytosis except that it involves large particles instead of mole- cules. 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 surface of the particle bind with receptors on the surface 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 intermediation of antibodies is called opsonization and is discussed further in Chapters 33 and 34. 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 16 UNIT I Introduction to Physiology: The Cell and General Physiology digestive vesicle is formed in which the enzymes begin hydrolyzing the proteins, carbohydrates, lipids, and other substances in the vesicle. The products of diges- tion are small molecules of amino acids, glucose, phosphate, and so on that can diffuse through the membrane of the vesicle into the cytoplasm. The undi- gested substances, called the residual body, are excreted through the cell membrane via the process of exocyto- sis, which is basically the opposite of endocytosis. 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 gran- ular ER, characterized by large numbers of ribosomes attached to the outer surface, is the site of protein for- mation. 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 protein molecules enter the ER, enzymes in the ER wall cause rapid changes, including congrega- tion of carbohydrates to form glycoproteins. In addition, the proteins are often cross-linked, folded, and short- ened to form more compact molecules. The ER also synthesizes lipids, especially phospholipid and cholesterol, which are incorporated into the lipid bilayer of the ER. Small ER vesicles, or transport vesicles, continually break off from the smooth reticulum. Most of these 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 vesic- ular spaces of the Golgi apparatus. Here, more carbohy- drates are added to the secretions, and the ER secretions are compacted. As the secretions pass toward the outer- most layers of the Golgi apparatus, the compaction and processing continue; finally, small and large vesicles break away from the Golgi apparatus, carrying with  The Cell and 17 Its Functions them the compacted secretory substances. These sub- stances 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 apparatus, however, are destined for intracellular use. For example, specialized portions of the Golgi appara- tus form lysosomes. Extraction of Energy from Nutrients by the Mitochondria (p. 21) The principal substances from which the cells extract energy are oxygen and one or more of the foodstuffs— carbohydrates, fats, proteins—that react with oxygen. In the human body, 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 influ- ence of enzymes that control the rates of reaction and channel the released energy in the proper direction. Oxidative Reactions Occur inside the Mitochondria, and the Energy Released Is Used to Form Mainly 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 the Mitochondria. After entry into the cells, glucose is sub- jected to enzymes in the cytoplasm that convert it to pyruvic acid, a process called glycolysis. Less than 5% of the ATP formed in the cell occurs via glycolysis. The pyruvic acid derived from carbohydrates, the fatty acids derived from lipids, and the amino acids 18 UNIT I Introduction to Physiology: The Cell and General Physiology derived from proteins are all eventually converted to the compound acetyl-coenzyme A (acetyl-CoA) in the matrix of mitochondria. This substance is then acted on by another series of enzymes in a sequence of chem- ical reactions called the citric acid cycle, or Krebs cycle. In the citric acid cycle, acetyl-CoA is split into hydrogen ions and carbon dioxide. The hydrogen ions are highly 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 large amounts of ADP to ATP. This requires large numbers of protein enzymes that are integral parts of the mitochondria. The initial event in the formation of ATP is removal of an electron from the hydrogen atom, thereby con- verting it to a hydrogen ion. The terminal event is move- ment of the hydrogen ion through large globular proteins called ATP synthetase, which protrude through the membranes of the mitochondrial membranous shelves, which themselves protrude into the mitochon- drial matrix. ATP synthetase is an enzyme that uses the energy and movement of the hydrogen ions to effect the conversion of ADP to ATP, and hydrogen ions com- bine with oxygen to form water. The newly formed ATP is transported 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 pro- motes three types of cell function: (1) membrane trans- port, 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. 23) The most important type of movement that occurs in the body is that of the specialized muscle cells in skele- tal, cardiac, and smooth muscle, which constitute almost 50% of the entire body mass. Two other types of movement occur in other cells: ameboid locomotion and ciliary movement. Ameboid Locomotion Is the Movement of an Entire Cell in Relation to Its Surroundings. An example of ameboid locomotion is the movement of white blood  The Cell and 19 Its Functions 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 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 of attachment. This attachment is effected by receptor proteins that line the insides of the exocytotic vesicles. The second requirement for locomotion is the pres- ence of the 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 network contracts when it binds with another pro- tein, 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 ameboid movement is the process called chemotaxis, which results from the appearance of certain chemical substances 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 (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 there are at least two necessary factors: (1) the presence of ATP and (2) the appropriate ionic conditions, including appropriate concentrations of magnesium and calcium. CHAPTER 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction Genes in 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 the forma- tion of ribonucleic acid (RNA). The RNA, in turn, spreads throughout the cells to control the formation of a specific protein. The entire process, from transcrip- tion of the genetic code in the nucleus to translation of the RNA code and formation or 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 cellular proteins. 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) deoxyri- bose (a sugar), and (3) four nitrogenous bases: two pur- ines (adenine and guanine) and two pyrimidines (thymine and cytosine). The first stage in the formation of DNA is the com- bination of one molecule of phosphoric acid, one mol- ecule of deoxyribose, and one of the four bases to form a nucleotide. 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 ade- nine 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, and these code words control the 20  Genetic Control of Protein Synthesis, Cell Function, 21 and Cell Reproduction Plasma Nuclear membrane envelope Nucleus DNA Gene (DNA) DNA Transcription transcription RNA RNA formation RNA splicing Translation RNA transport Protein formation Translation of Ribosomes messenger RNA Cell Cell Protein structure enzymes Cytosol Cell function Figure 3–1. General schema by which the genes control cell function. 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 gua- nine, 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 suc- cessive code words of the DNA strand is known as the genetic code. DNA Code in the Cell 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 of the functions 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 cyto- plasm. This is achieved through RNA, the formation of which is controlled by DNA. During this process the code of DNA is transferred to RNA, a process called 22 UNIT I Introduction to Physiology: The Cell and General Physiology transcription. 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 Tem- plate. During the synthesis of RNA the two strands of the DNA molecule separate, and one of the two strands is used as a template for the synthesis of RNA. The code triplets in the DNA cause the formation of com- plementary code triplets (called codons) in the 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 synthesis of RNA is activation of the nucleotides. This 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 influ- ence 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.  Genetic Control of Protein Synthesis, Cell Function, 23 and Cell Reproduction 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; this causes the polymerase to break away from the DNA strand. The RNA strand is then released into the nucleoplasm. The code present in the DNA strand is transmitted in complementary form to the RNA molecule as follows: DNA Base RNA Base Guanine Cytosine Cytosine Guanine Adenine Uracil Thymine Adenine There Are Four Types of RNA. Each of the four types of RNA plays a different role in protein formation: (1) messenger RNA (mRNA) carries the genetic code to the cytoplasm to control the formation of proteins; (2) ribosomal RNA, along with proteins, forms the ribo- somes, the structures in which protein molecules are assembled; (3) transfer RNA (tRNA) transports activated amino acids to the ribosomes to be used in the assembly of the proteins; and (4) 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. Translation Is Synthesis of Polypeptides on the Ribosomes from the Genetic Code Contained in mRNA (p. 33) 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 24 UNIT I Introduction to Physiology: The Cell and General Physiology bind together to form chemical bonds called peptide linkages. The mRNA does not recognize the different types of amino acid 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 codon appears and indicates completion of the process, and the protein is released into the cytoplasm or through the membrane of the endoplas- mic reticulum to the interior. Control of Gene Function and Biochemical Activity in Cells (p. 35) The genes control the function of each cell by deter- mining the relative proportion of the various types of enzymes and structural proteins that are formed. Regu- lation of gene expression covers the entire process from transcription of the genetic code in the nucleus to the formation or 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 7 bases (TATAAAA) called the TATA box, the binding site for the TATA-binding protein (TBP) 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 as well as RNA polymerase 2 to facilitate tran- scription of the DNA into RNA. This basal promoter is found in all protein coding genes 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 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  Genetic Control of Protein Synthesis, Cell Function, 25 and Cell Reproduction transcription factor binding sites in the upstream pro- moter 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 a great distance from the gene they act on or even on a different chromosome. However, although enhancers may be located a great distance away from their target gene, they may be relatively close when DNA is coiled in the nucleus. It is estimated 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 inhi- bition of the promoter that is responsible for its synthe- sis. 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. There are other mechanisms available for control of transcription by the promoter, including the following: 1. A promoter may be controlled by transcription factors located elsewhere in the genome. 2. In some instances, the same regulatory protein func- tions as an activator for one promoter and as a repressor for another, allowing different promoters to be controlled at the same time by the same regu- latory 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. So long as the 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 decompacted, allowing RNA transcription. Even then, specific transcriptor factors control the actual rate of transcription by the promoter in the chromosome. The DNA-Genetic System Also Controls Cell Reproduction (p. 37) 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. 26 UNIT I Introduction to Physiology: The Cell and General Physiology In this way, the genetic system controls each stage of the development of the human from the single-cell fer- tilized 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 automatically divides via mito- sis 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 lifetime of the human body for nerve cells. Cell Reproduction Begins with Replication of DNA. Only after all of the DNA in the chromosomes has been replicated can mitosis take place. 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 repli- cation 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 occurs 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 strand of DNA remains attached by loose hydrogen bonding to the original DNA strand that is used as its template. Two DNA helixes are formed, therefore, that 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 inappro- priate DNA nucleotides have been matched up with the nucleotides of the original template strand, special enzymes cut out the defective areas and replace them with the appropriate complementary nucleotides. Because of proofreading and repair, the transcription  Genetic Control of Protein Synthesis, Cell Function, 27 and Cell Reproduction 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 each packaged as a single chromosome. The human cell contains 46 chromo- somes arranged in 23 pairs. In addition to the DNA in the chromosome, there is a large amount of protein composed mainly of histones, around which small seg- ments of each DNA helix are coiled. During mitosis, the successive coils are packed against each other, allowing the long DNA molecule to be packaged in a coiled and folded arrangement. Replication of the chro- mosomes in their entirety occurs soon after replication of the DNA helixes. The two newly formed chromo- somes remain temporarily attached to each other at a point called the centromere, which is located near their center. These duplicated but still-attached chromo- somes are called chromatids. Mitosis Is the Process by which the Cell Splits into Two New Daughter Cells. Two pairs of centrioles, which are small structures that lie close to one pole of the nucleus, begin to move apart from each other. This movement is caused by successive polymerization of protein microtubules growing outward from each pair of centrioles. As the tubules grow, they push one pair of centrioles toward one pole of the cell and the other toward the opposite pole. At the same time, other microtubules grow radially away from each of the cen- triole pairs, forming a spiny star called the aster at each end of the cell. The complex of microtubules extending between the centriole pairs is called the spindle, and the entire set of microtubules plus the pairs of centrioles is called the mitotic apparatus. Mitosis then proceeds through several phases. Prophase is the beginning of mitosis. While the spin- dle is forming, the chromosomes of the nucleus become condensed into well-defined chromosomes. Prometaphase is the stage at which the growing microtubular spines of the aster puncture and frag- ment the nuclear envelope. At the same time, the microtubules from the aster become attached to the chromatids at the centromere, where the paired chromatids are still bound to each other. Metaphase is the stage at which the two asters of the mitotic apparatus are pushed farther and farther apart by additional growth of the mitotic spindle. 28 UNIT I Introduction to Physiology: The Cell and General Physiology Simultaneously, the chromatids are pulled tightly by the attached microtubules to the center of the cell, lining up to form the equatorial plate of the mitotic spindle. Anaphase is the stage at which the two chromatids of each chromosome are pulled apart at the centro- mere. Thus all 46 pairs of chromosomes are sepa- rated, forming two sets of 46 daughter chromosomes. Telophase is the stage at which the two sets of daugh- ter chromosomes are pulled completely apart. Then the mitotic apparatus dissolves, and a new nuclear membrane develops around each set of chromosomes. Cell Differentiation Allows Different Cells of the Body to Perform Different Functions. As a human develops from a fertilized ovum, the ovum divides repeatedly until trillions of cells are formed. Gradually, however, the new cells differentiate from each other, with certain cells having different genetic characteristics from other cells. This differentiation process occurs as a result of inactivation of certain genes and activation of others during successive stages of cell division. This process of differentiation leads to the ability of different cells in the body to perform different functions.  II Membrane Physiology, Nerve, and Muscle 4. Transport of Substances through Cell Membranes 5. Membrane Potentials and Action Potentials 6. Contraction of Skeletal Muscle 7. Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling 8. Excitation and Contraction of Smooth Muscle This page intentionally left blank  CHAPTER 4 Transport of Substances through Cell Membranes Differences between the composition of intracellular and extracellular fluids are caused by transport mechanisms of cell membranes. These differences include the following: Extracellular fluid has a high sodium concentration, high chloride concentration, and low potassium con- centration. The opposite is true of intracellular fluid. The concentrations of phosphates and proteins in intracellular fluid are greater than those in extracellu- lar fluid. The Cell Membrane Consists of a Lipid Bilayer with “Floating” Protein Molecules. The lipid bilayer constitu- tes a barrier for the movement of most water-soluble sub- stances. However, most lipid-soluble substances can pass directly through the lipid bilayer. Protein molecules in the lipid bilayer constitute an alternate transport pathway. Channel proteins provide a watery pathway for mole- cules to move through the membrane. Carrier proteins bind with specific molecules and then undergo conformational changes that move molecules through the membrane. Transport through the Cell Membrane Occurs through Diffusion or Active Transport Diffusion means random movement of molecules either through intermolecular spaces in the cell membrane or in combination with a carrier protein. The energy that causes diffusion is the energy of the normal kinetic motion of matter. Active transport means movement of substances across the membrane in combination with a carrier protein but also against an electrochemical gradient. This process requires a source of energy in addition to kinetic energy. Diffusion (p. 46) Diffusion Is the Continual Movement of Molecules in Liquids or Gases. Diffusion through the cell membrane is divided into the following two subtypes: Simple diffusion means that molecules move through a membrane without binding with carrier proteins. Simple diffusion can occur by way of two pathways: 31 32 UNIT II Membrane Physiology, Nerve, and Muscle (1) through the interstices of the lipid bilayer and (2) through watery channels in transport proteins that span the cell membrane. Facilitated diffusion requires a carrier protein. The carrier protein aids in passage of molecules through the membrane, probably by binding chemically with them and shuttling them through the membrane in this form. The Rate of Diffusion of a Substance through the Cell Membrane Is Directly Proportional to Its Lipid Solubility. The lipid solubilities of oxygen, nitrogen, carbon diox- ide, anesthetic gases, and most alcohols are so high they can dissolve directly in the lipid bilayer and diffuse through the cell membrane. Water and Other Lipid-Insoluble Molecules Diffuse through Protein Channels in the Cell Membrane. Water readily penetrates the cell membrane and can also pass through transmembrane protein channels. Other lipid- insoluble molecules (mainly ions) can pass through the water-filled protein channels in the same way as water molecules if they are sufficiently small. Protein Channels Have Selective Permeability for Transport of One or More Specific Molecules. This per- meability results from the characteristics of the channel itself, such as its diameter, its shape, and the nature of the electrical charges along its inside surfaces. Gating of Protein Channels Provides a Means for Controlling Their Permeability. The gates are thought to be gatelike extensions of the transport protein mole- cule, which can close over the channel opening or be lifted from the opening by a conformational change in the protein molecule itself. The opening and closing of gates are controlled in two principal ways: Voltage gating. In this instance, the molecular confor- mation of the gate responds to the electrical potential across the cell membrane. For example, the normal negative charge on the inside of the cell membrane causes the sodium gates to remain tightly closed. When the inside of the membrane loses its negative charge (becomes less negative), these gates open allowing sodium ions to pass inward through the sodium channels. The opening of sodium channel gates is the basic cause of action potentials in nerves. Chemical gating. Some protein channel gates are opened by the binding of another molecule with the protein; this causes a conformational change in  Transport of Substances through 33 Cell Membranes the protein molecule that opens or closes the gate. This is called chemical (or ligand) gating. One of the most important instances of chemical gating is the effect of acetylcholine on the “acetylcholine chan- nel” of the neuromuscular junction. Facilitated Diffusion Is Also Called Carrier-Mediated Diffusion. A substance transported in this manner usu- ally cannot pass through the cell membrane without the assistance of a specific carrier protein. Facilitated diffusion involves the following two steps: (1) the molecule to be transported enters a blind- ended channel and binds to a specific receptor and (2) a conformational change occurs in the carrier protein, so the channel now opens to the opposite side of the membrane. Facilitated diffusion differs from simple diffusion in the following important way. The rate of simple dif- fusion increases proportionately with the concentra- tion of the diffusing substance. With facilitated diffusion, the rate of diffusion approaches a maxi- mum as the concentration of the substance increases. This maximum rate is dictated by the rate at which the carrier protein molecule can undergo the confor- mational change. Among the most important substances that cross cell membranes through facilitated diffusion are glucose and most of the amino acids. Factors That Affect the Net Rate of Diffusion (p. 50) Substances Can Diffuse in Both Directions through the Cell Membrane. Therefore, what is usually important is the net rate of diffusion of a substance in the desired direction. This net rate is determined by the following factors: Permeability. The permeability of a membrane for a given substance is expressed as the net rate of diffu- sion of the substance through each unit area of the membrane for a unit concentration difference between the two sides of the membrane (when there are no electrical or pressure differences). Concentration difference. The rate of net diffusion through a cell membrane is proportional to the dif- ference in concentration of the diffusing substance on the two sides of the membrane. 34 UNIT II Membrane Physiology, Nerve, and Muscle Electrical potential. If an electrical potential is applied across a membrane, the ions move through the membrane because of their electrical charges. When large amounts of ions have moved through the mem- brane, a concentration difference of the same ions develops in the direction opposite to the electrical potential difference. When the concentration differ- ence rises to a sufficiently high level, the two effects balance each other creating a state of electrochemical equilibrium. The electrical difference that balances a given concentration difference can be determined with the Nernst equation. Osmosis across Selectively Permeable Membranes— “Net Diffusion of Water” (p. 51) Osmosis Is the Process of Net Movement of Water Caused by a Concentration Difference of Water. Water is the most abundant substance to diffuse through the cell membrane. However, the amount that diffuses in each direction is so precisely balanced under normal conditions that not even the slightest net movement of water occurs. Therefore, the volume of a cell remains constant. However, a concentration difference for water can develop across a cell membrane. When this happens, net movement of water occurs across the cell membrane, causing the cell to either swell or shrink, depending on the direction of the net movement. The pressure difference required to stop osmosis is the osmotic pressure. The Osmotic Pressure Exerted by Particles in a Solu- tion Is Determined by the Number of Particles per Unit Volume of Fluid and Not by the Mass of the Particles. On average, the kinetic energy of each molecule or ion that strikes a membrane is about the same regard- less of its molecular size. Consequently, the factor that determines the osmotic pressure of a solution is the concentration of the solution in terms of number of particles per unit volume but not in terms of mass of the solute. The Osmole Expresses Concentration in Terms of Number of Particles. One osmole is 1 g molecular weight of undissociated solute. Thus 180 g of glucose, which is 1 g molecular weight of glucose, is equal to 1 osmole of glucose because glucose does not dissoci- ate. A solution that has 1 osmole of solute dissolved in each kilogram of water is said to have an osmolality of 1 osmole per kilogram, and a solution that has  Transport of Substances through 35 Cell Membranes 1/1000 osmole dissolved per kilogram has an osmolality of 1 milliosmole per kilogram. The normal osmolality of the extracellular and intracellular fluids is about 300 milliosmoles per kilogram, and the osmotic pres- sure of these fluids is about 5500 mm Hg. “Active Transport” of Substances through Membranes (p. 52) Active Transport Can Move a Substance against an Elec- trochemical Gradient. An electrochemical gradient is the sum of all the diffusion forces acting at the mem- brane—the forces caused by a concentration difference, an electrical difference, and a pressure difference. That is, substances cannot diffuse “uphill.” When a cell membrane moves a substance uphill against a concen- tration gradient (or uphill against an electrical or pres- sure gradient), the process is called active transport. Active Transport Is Divided into Two Types According to the Source of the Energy Used to Effect the Transport. In both instances, transport depends on carrier proteins that penetrate the membrane, which is also true for facilitated diffusion. Primary active transport. The energy is derived directly from the breakdown of adenosine triphos- phate (ATP) or some other high-energy phosphate compound. Secondary active transport. The energy is derived sec- ondarily from energy that has been stored in the form of ionic concentration differences between the two sides of a membrane, originally created by primary active transport. The sodium electrochemical gradient drives most secondary active transport processes. Primary Active Transport (p. 53) The Sodium-Potassium (Naþ-Kþ) Pump Transports Sodium Ions out of Cells and Potassium Ions into Cells. This pump is present in all cells of the body, and it is responsible for maintaining the sodium and potassium concentration differences across the cell membrane as well as for establishing a negative electrical potential inside the cells. The pump operates in the following manner. Three sodium ions bind to a carrier protein on the inside of the cell, and two potassium ions bind to the carrier protein on the outside of the cell. The carrier protein has ATPase activity, and the simul- taneous binding of sodium and potassium ions causes 36 UNIT II Membrane Physiology, Nerve, and Muscle the ATPase function of the protein to become acti- vated. This then cleaves one molecule of ATP, splitting it to form adenosine diphosphate (ADP) and liberating a high-energy phosphate bond of energy. This energy is then believed to cause a conformational change in the protein carrier molecule, extruding the sodium ions to the outside and the potassium ions to the inside. The Naþ-Kþ Pump Controls Cell Volume. The Naþ- þ K pump transports three molecules of sodium to the outside of the cell for every two molecules of potassium pumped to the inside. This continual net loss of ions from the cell interior initiates an osmotic force to move water out of the cell. Furthermore, when the cell begins to swell, this automatically activates the Naþ-Kþ pump, moving to the exterior still more ions that are carrying water with them. Therefore, the Naþ-Kþ pump per- forms a continual surveillance role in maintaining nor- mal cell volume. Active Transport Saturates in the Same Way That Facilitated Diffusion Saturates. When the difference in concentration of the substance to be transported is small, the rate of transport rises approximately in pro- portion to increases in its concentration. At high con- centrations, the rate of transport is limited by the rates at which the chemical reactions of binding, release, and carrier conformational changes can occur. Co-Transport and Counter-Transport Are Two Forms of Secondary Active Transport. When sodium ions are transported out of cells by primary active transport, a large concentration gradient of sodium normally devel- ops. This gradient represents a storehouse of energy because the excess sodium outside the cell membrane is always attempting to diffuse to the cell interior. Co-transport. The diffusion energy of sodium can pull other substances along with the sodium (in the same direction) through the cell membrane using a special carrier protein. Counter-transport. The sodium ion and substance to be counter-transported move to opposite sides of the membrane, with sodium always moving to the cell interior. Here again, a protein carrier is required. Glucose and Amino Acids Can Be Transported into Most Cells through Sodium Co-Transport. The transport carrier protein has two binding sites on its exterior side—one for sodium and one for glucose or amino acids. Again, the concentration of sodium ions is very  Transport of Substances through 37 Cell Membranes high on the outside and very low on the inside, providing the energy for the transport. A special prop- erty of the transport protein is that the conformational change to allow sodium movement to the cell interior does not occur until a glucose or amino acid molecule also attaches. Calcium and Hydrogen Ions Can Be Transported out of Cells through the Sodium Counter-Transport Mechanism Calcium counter-transport occurs in most cell mem- branes, with sodium ions moving to the cell interior and calcium ions moving to the exterior, both bound to the same transport protein in a counter-transport mode. Hydrogen counter-transport occurs especially in the proximal tubules of the kidneys, where sodium ions move from the lumen of the tubule to the interior of the tubular cells, and hydrogen ions are counter- transported into the lumen. CHAPTER 5 Membrane Potentials and Action Potentials Electrical potentials exist across the membranes of essen- tially all cells of the body. In addition, nerve and muscle cells are “excitable” (i.e., capable of self-generating electri- cal impulses at their membranes). The present discussion is concerned with membrane potentials that are gener- ated both at rest and during action potentials by nerve and muscle cells. Basic Physics of Membrane Potentials (p. 57) A Concentration Difference of Ions across a Selectively Permeable Membrane Can Produce a Membrane Potential Potassium diffusion potential. Suppose a cell mem- brane is permeable to potassium ions but not to any other ions. Potassium ions tend to diffuse outward because of the high potassium concentration inside the cell. Because potassium ions are positively charged, the loss of potassium ions from the cell cre- ates a negative potential inside the cell. Within a few milliseconds, the potential change becomes suffi- ciently great to block further net diffusion of potas- sium despite the high potassium ion concentration gradient. In the normal large mammalian nerve fiber, the potential difference required to stop further net diffusion is about
94 millivolts. Sodium diffusion potential. Now suppose a cell mem- brane is permeable to sodium ions but not to any other ions. Sodium ions tend to diffuse into the cell because of the high sodium concentration outside the cell. Diffusion of sodium ions into the cell creates a positive potential inside the cell. Again, the mem- brane potential rises sufficiently high within milli- seconds to block further net diffusion of sodium ions into the cell; however, this time, for the large mammalian nerve fiber, the potential is about þ61 millivolts. The Nernst Equation Describes the Relation of Diffu- sion Potential to Concentration Difference. The mem- brane potential that prevents net diffusion of an ion in either direction through the membrane is called the 38  Membrane Potentials and 39 Action Potentials Nernst potential for that ion. The following is the Nernst equation:   concentration inside EMFðmillivoltsÞ ¼  61 log concentration outside where EMF is the electromotive force. The sign of the potential is positive (þ) if the ion under consideration is a negative ion and negative (–) if it is a positive ion. The Goldman Equation Is Used to Calculate the Diffusion Potential When the Membrane Is Permeable to Several Different Ions. In this case, the diffusion potential that develops depends on three factors: (1) the polarity of the electrical charge of each ion, (2) the permeability of the membrane (P) to each ion, and (3) the concentrations (C) of the respective ions on the inside (i) and outside (o) of the membrane. The following is the Goldman equation: EMFðmillivoltsÞ ¼   CNaþ i PNaþ þ CKþ i PKþ þ CCl
o PCl

61 log CNaþ o PNaþ þ CKþ o PKþ þ CCl
i PCl
Note the following features and implications of the Goldman equation: Sodium, potassium, and chloride ions are most importantly involved in the development of mem- brane potentials in neurons and muscle fibers as well as in the neuronal cells in the central nervous system. The degree of importance of each ion in determining the voltage is proportional to the membrane perme- ability for that particular ion. A positive ion concentration gradient from inside the membrane to the outside causes electronegativity inside the membrane. Resting Membrane Potential of Nerves (p. 59) The Resting Membrane Potential Is Established by the Diffusion Potentials, Membrane Permeability, and Elec- trogenic Nature of the Naþ-Kþ Pump Potassium diffusion potential. A high ratio of potas- sium ions from inside to outside the cell, 35:1, pro- duces a Nernst potential of
94 millivolts according to the Nernst equation. 40 UNIT II Membrane Physiology, Nerve, and Muscle Sodium diffusion potential. The ratio of sodium ions from inside to outside the membrane is 0.1, which gives a calculated Nernst potential of þ61 millivolts. Membrane permeability. The permeability of the nerve fiber membrane to potassium is about 100 times as great as that to sodium, so the diffusion of potas- sium contributes far more to the membrane potential. The use of this high value of permeability in the Gold- man equation gives an internal membrane potential of
86 millivolts, which is near the potassium diffusion potential of
94 millivolts. Electrogenic nature of the Naþ-Kþ pump. The Naþ-Kþ pump transports three sodium ions to the outside of the cell for each two potassium ions pumped to the inside, which causes a continual loss of positive charges from inside the membrane. Therefore the Naþ-Kþ pump is electrogenic because it produces a net deficit of positive ions inside the cell; this causes a negative charge of about
4 millivolts inside the cell membrane. Nerve Action Potential (p. 60) Nerve signals are transmitted by action potentials, which are rapid changes in the membrane potential. Each action potential begins with a sudden change from the normal resting negative potential to a positive membrane potential and then ends with an almost equally rapid change back to the resting negative potential. The successive stages of the action potential are as follows: Resting stage. This is the resting membrane potential before the action potential occurs. Depolarization stage. At this time, the membrane suddenly becomes permeable to sodium ions, allow- ing tremendous numbers of positively charged sodium ions to flow to the interior of the axon, and the potential rises rapidly in the positive direction. Repolarization stage. Within a few 10,000ths of a sec- ond after the membrane becomes highly permeable to sodium ions the sodium channels begin to close and the potassium channels open more than they normally do. Then rapid diffusion of potassium ions to the exterior re-establishes the normal negative resting membrane potential.  Membrane Potentials and 41 Action Potentials Voltage-Gated Sodium and Potassium Channels Are Activated and Inactivated during the Course of an Action Potential. The necessary factor for both depolarization and repolarization of the nerve membrane during the action potential is the voltage-gated sodium channel. The voltage-gated potassium channel also plays an important role in increasing the ra