1.Standard Atomic WeightsBased on the assigned relative mass of C = 12. For the sake of completeness, all known elements are included in the list. Sev- 12eral of those more recently discovered are represented only by the unstable isotopes. In each case, the values in parentheses inthe atomic weight column are the mass numbers of the most stable isotopes. Atomic Atomic Atomic Atomic Name Symbol No.Weight Valence Name SymbolNo. WeightValenceActinium Ac 89 227.028 ... Mercury Hg 80 200.591,2Aluminum Al 1326.9815 3 (hydrargyrum)AmericiumAm 95(243)3,4,5,6 MolybdenumMo 4295.94 3,4,6Antimony Sb 51 121.753,5 Neodymium Nd 60 144.24 3(stibium)NeonNe 1020.1179 0ArgonAr 1839.9480Neptunium Np 93 237.0482 4,5,6ArsenicAs 3374.92163,5 NickelNi 2858.692,3Astatine At 85(210)1,3,5,7 Niobium Nb 4192.90643,5Barium Ba 56 137.33 2 (columbium)BerkeliumBk 97(247)3,4 NitrogenN7 14.00673,5BerylliumBe4 9.0122 2NobeliumNo 102(259) ...BismuthBi 83 208.980 3,5 OsmiumOs76190.2 2,3,4,8BoronB 510.81 3OxygenO8 15.9994 2BromineBr 3579.904 1,3,5,7 Palladium Pd46106.42 2,4,6CadmiumCd 48 112.41 2PhosphorusP 15 30.97383,5CalciumCa 2040.08 2PlatinumPt78195.082,4CaliforniumCf 98(251)... Plutonium Pu94 (244)3,4,5,6Carbon C 612.011 2,4 PoloniumPo84 (209)...Cerium Ce 58 140.123,4 Potassium K 19 39.0983 1Cesium Cs 55 132.9054 1 (kalium)Chlorine Cl 1735.453 1,3,5,7 PraseodymiumPr 59 140.9083Chromium Cr 2451.9962,3,6PromethiumPm 61(145) 3Cobalt Co 2758.93322,3 ProtactiniumPa 91 231.0359...ColumbiumRadiumRa 88 226.0252(see Niobium)Radon Rn 86(222) 0Copper Cu29 63.546 1,2 Rhenium Re 75 186.207 ...Curium Cm96 (247) 3Rhodium Rh 45 102.9063Dysprosium Dy66162.50 3RubidiumRb 3785.4678 1EinsteiniumEs99 (252)... Ruthenium Ru 44 101.073,4,6,8Erbium Er68167.26 3SamariumSm 62 150.362,3Europium Eu63151.962,3 ScandiumSc 2144.9559 3FermiumFm 100 (257)... SeleniumSe 3478.96 2,4,6Fluorine F9 18.9984 1Silicon Si 1428.0855 4Francium Fr87 (223) 1SilverAg 47 107.8681Gadolinium Gd64157.25 3 (argentum)GalliumGa31 69.722,3 SodiumNa 1122.9898 1GermaniumGe32 72.59 4 (natrium)Gold Au79196.967 1,3 Strontium Sr 3887.62 2(aurum)SulfurS1632.06 2,4,6HafniumHf 72 178.49 4TantalumTa 73 180.9479 5Helium He2 4.0026 0TechnetiumTc 43 (98)6,7HolmiumHo 67 164.9303Tellurium Te 52 127.60 2,4,6Hydrogen H 1 1.0079 1Terbium Tb 65 158.9253Indium In 49 114.82 3ThalliumTl 81 204.383 1,3Iodine I53 126.905 1,3,5,7 Thorium Th 90 232.0384IridiumIr 77 192.223,4 Thulium Tm 69 168.9343Iron Fe 2655.847 2,3 Tin Sn 50 118.712,4(ferrum)(stannum)KryptonKr36 83.80 0TitaniumTi 2247.883,4LanthanumLa57138.9063TungstenW74 183.85 6Lawrencium Lr 103 (260)...(wolfram)Lead Pb82207.2 2,4 Uranium U92 238.029 4,6 (plumbum) VanadiumV2350.94153,5LithiumLi 36.9411Xenon Xe 54 131.29 0Lutetium Lu71174.9673Ytterbium Yb 70 173.042,3MagnesiumMg12 24.3052Yttrium Y3988.9059 3ManganeseMn25 54.9380 2,3,4,6,7ZincZn 3065.39 2MendeleviumMd 101 (258)... Zirconium Zr 4091.2244Modified and reproduced, with permission from Lide DR (editor-in-chief): CRC Handbook of Chemistry and Physics,83rd ed. CRC Press, 20022003.

2. a LANGE medical bookReview ofMedical Physiologytwenty-second editionWilliam F. Ganong, MDJack and DeLoris Lange Professor of Physiology EmeritusUniversity of CaliforniaSan FranciscoLange Medical Books/McGraw-HillMedical Publishing DivisionNew York Chicago San Francisco Lisbon London Madrid Mexico CityMilan New Deli San Juan Seoul Singapore Sydney Toronto 3. Review of Medical Physiology, Twenty-Second EditionCopyright 2005 by The McGraw-Hill Companies, Inc. All rights reserved. Printed in the United States ofAmerica. Except as permitted under the United States Copyright Act of 1976, no part of this publicationmay be reproduced or distributed in any form or by any means, or stored in a data base or retrieval system, withoutthe prior written permission of the publisher.Previous editions copyright 2003, 2001 by The McGraw-Hill Companies, Inc.; copyright 1999, 1997, 1995,1993, 1991, by Appleton & Lange; copyright 1963 through 1989 by Lange Medical Publications.1234567890 DOC/DOC 098765ISBN 0-07-144040-2ISSN 0892-1253Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The author and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the author nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.The book was set in Adobe Garamond by Rainbow Graphics.The editors were Janet Foltin, Harriet Lebowitz, and Regina Y. Brown.The production supervisor was Catherine H. Saggese.The cover designer was Mary McKeon.The art manager was Charissa Baker.The index was prepared by Katherine Pitcoff.RR Donnelley was printer and binder.This book is printed on acid-free paper. 4. ContentsPreface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiSECTION I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 1. The General & Cellular Basis of Medical Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Introduction 1 Transport Across Cell Membranes 28General Principles 1 The Capillary Wall 35Functional Morphology of the Cell 8Intercellular Communication 36Structure & Function ofHomeostasis 48 DNA & RNA 18Aging 48Section I References 49SECTION II. PHYSIOLOGY OF NERVE & MUSCLE CELLS . . . . . . . . . . . . . . . . . . . . . . . . .51 2. Excitable Tissue: Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51Introduction 51 Properties of Mixed Nerves 60Nerve Cells 51Nerve Fiber Types & Function 60Excitation & Conduction 54Neurotrophins 61Ionic Basis of Excitation Neuroglia 63 & Conduction 58 3. Excitable Tissue: Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .65Introduction 65Cardiac Muscle 78Skeletal Muscle 65 Morphology 78Morphology 65Electrical Properties 78Electrical Phenomena Mechanical Properties 78& Ionic Fluxes 68Metabolism 81Contractile Responses 68 Pacemaker Tissue 81Energy Sources & Metabolism 74 Smooth Muscle 82Properties of Skeletal Muscles Morphology 82in the Intact Organism 75Visceral Smooth Muscle 82 Multi-Unit Smooth Muscle 84 4. Synaptic & Junctional Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .85Introduction 85Principal Neurotransmitter Systems 94Synaptic Transmission 85 Synaptic Plasticity & Learning 116Functional Anatomy 85Neuromuscular Transmission 116Electrical Events in PostsynapticNeuromuscular Junction 116 Neurons 88Nerve Endings in Smooth & CardiacInhibition & FacilitationMuscle 118 at Synapses 91Denervation Hypersensitivity 119Chemical Transmission of Synaptic Activity 94iii 5. iv/CONTENTS5. Initiation of Impulses in Sense Organs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Introduction 121Generation of Impulses in Different Nerves 123 Sense Organs & Receptors 121Coding of Sensory Information 124 The Senses 121 Section II References 127SECTION III. FUNCTIONS OF THE NERVOUS SYSTEM . . . . . . . . . . . . . . . . . . . . . . . . . . . 1296. Reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Introduction 129 Polysynaptic Reflexes: The Withdrawal Reflex 134 Monosynaptic Reflexes: General Properties of Reflexes 137 The Stretch Reflex 1297. Cutaneous, Deep, & Visceral Sensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Introduction 138Temperature 142 Pathways 138Pain 142 Touch 141 Other Sensations 147 Proprioception 1428. Vision. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 Introduction 148Responses in the Visual Pathways & Cortex 160 Anatomic Considerations 148 Color Vision 163 The Image-Forming Mechanism 152 Other Aspects of Visual Function 166 The Photoreceptor Mechanism 156 Eye Movements 1689. Hearing & Equilibrium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 Introduction 171Hearing 176 Anatomic Considerations 171 Vestibular Function 183 Hair Cells 175 10. Smell & Taste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 Introduction 185Taste 188 Smell 185 Receptor Organs & Pathways 188 11. Alert Behavior, Sleep, & the Electrical Activity of the Brain. . . . . . . . . . . . . . . . . . . . . . . . . . 192 Introduction 192 Evoked Cortical Potentials 193 The Thalamus & the CerebralThe Electroencephalogram 194Cortex 192Physiologic Basis of the EEG, Consciousness, The Reticular Formation & the Reticular& Sleep 196Activating System 192 12. Control of Posture & Movement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202 Introduction 202Spinal Integration 207 General Principles 202Medullary Components 210 Corticospinal & Corticobulbar Midbrain Components 211System 203 Cortical Components 212 Anatomy & Function 203Basal Ganglia 213 Posture-Regulating Systems 206Cerebellum 217 6. CONTENTS /v 13. The Autonomic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Introduction 223 Chemical Transmission at Autonomic Anatomic Organization of Autonomic Junctions 223Outflow 223 Responses of Effector Organs to Autonomic NerveImpulses 226 14. Central Regulation of Visceral Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 Introduction 232 Relation to Cyclic Phenomena 235 Medulla Oblongata 232Hunger 235 Hypothalamus 233 Thirst 240 Anatomic Considerations 233Control of Posterior Pituitary Secretion 242 Hypothalamic Function 234Control of Anterior Pituitary Secretion 248 Relation to Autonomic Function 234 Temperature Regulation 251 Relation to Sleep 235 15. Neural Basis of Instinctual Behavior & Emotions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 Introduction 256 Other Emotions 259 Anatomic Considerations 256Motivation & Addiction 260 Limbic Functions 256 Brain Chemistry & Behavior 261 Sexual Behavior 257 16. Higher Functions of the Nervous System: Conditioned Reflexes, Learning, & Related Phenomena . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 Introduction 266Learning & Memory 266 Methods 266 Functions of the Neocortex 272 Section III References 276SECTION IV. ENDOCRINOLOGY, METABOLISM, & REPRODUCTIVE FUNCTION . . . 279 17. Energy Balance, Metabolism, & Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 Introduction 279 Protein Metabolism 292 Energy Metabolism 279Fat Metabolism 298 Intermediary Metabolism 282Nutrition 311 Carbohydrate Metabolism 285 18. The Thyroid Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 Introduction 317Effects of Thyroid Hormones 323 Anatomic Considerations 317 Regulation of Thyroid Secretion 326 Formation & Secretion Clinical Correlates 328of Thyroid Hormones 317 Transport & Metabolism of ThyroidHormones 321 19. Endocrine Functions of the Pancreas & Regulation of Carbohydrate Metabolism . . . . . . . . . 333 Introduction 333Fate of Secreted Insulin 335 Islet Cell Structure 333Effects of Insulin 336 Structure, Biosynthesis, & SecretionMechanism of Action 338 of Insulin 334Consequences of Insulin Deficiency 340 7. vi/CONTENTSInsulin Excess 344 Effects of Other Hormones & ExerciseRegulation of Insulin Secretion 345 on Carbohydrate Metabolism 351Glucagon 348 Hypoglycemia & Diabetes Mellitus in Humans 353Other Islet Cell Hormones 350 20. The Adrenal Medulla & Adrenal Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356 Introduction 356 Physiologic Effects of Adrenal Morphology 356 Glucocorticoids 369 Adrenal Medulla 358Pharmacologic & Pathologic Effects Structure & Function of Medullaryof Glucocorticoids 370Hormones 358Regulation of Glucocorticoid Regulation of Adrenal MedullarySecretion 372Secretion 361 Effects of Mineralocorticoids 375 Adrenal Cortex 361 Regulation of Aldosterone Secretion 377 Structure & Biosynthesis ofRole of Mineralocorticoids in theAdrenocortical Hormones 361 Regulation of Salt Balance 380 Transport, Metabolism, & Excretion Summary of the Effects ofof Adrenocortical Hormones 366Adrenocortical Hyper- Effects of Adrenal Androgens & Hypofunction in Humans 380& Estrogens 368 21. Hormonal Control of Calcium Metabolism & the Physiology of Bone . . . . . . . . . . . . . . . . . 382 Introduction 382The Parathyroid Glands 390 Calcium & Phosphorus Metabolism 382 Calcitonin 393 Bone Physiology 383 Effects of Other Hormones & Humoral Agents on Vitamin D & theCalcium Metabolism 395Hydroxycholecalciferols 387 22. The Pituitary Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 Introduction 396Physiology of Growth 404 Morphology 396Pituitary Insufficiency 408 Intermediate-Lobe Hormones 397Pituitary Hyperfunction in Humans 409 Growth Hormone 398 23. The Gonads: Development & Function of the Reproductive System . . . . . . . . . . . . . . . . . . . 411 Introduction 411 Gametogenesis & Ejaculation 424 Sex Differentiation & Development 411Endocrine Function of the Testes 428 Chromosomal Sex 411Control of Testicular Function 431 Embryology of the HumanAbnormalities of Testicular Function 433 Reproductive System 413 The Female Reproductive System 433 Aberrant Sexual Differentiation 414The Menstrual Cycle 433 Puberty 418Ovarian Hormones 438 Precocious & Delayed Puberty 420 Control of Ovarian Function 444 Menopause 421Abnormalities of Ovarian Function 447 Pituitary Gonadotropins & Prolactin 421 Pregnancy 448 The Male Reproductive System 424Lactation 451 Structure 424 8. CONTENTS / vii24. Endocrine Functions of the Kidneys, Heart, & Pineal Gland . . . . . . . . . . . . . . . . . . . . . . . . . 454Introduction 454 Hormones of the Heart & Other NatriureticThe Renin-Angiotensin System 454Factors 460Erythropoietin 459 Pineal Gland 462Section IV References 465SECTION V. GASTROINTESTINAL FUNCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46725. Digestion & Absorption. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467Introduction 467Lipids 473Carbohydrates 467 Absorption of Water & Electrolytes 475Proteins & Nucleic Acids 471Absorption of Vitamins & Minerals 47726. Regulation of Gastrointestinal Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479Introduction 479 Exocrine Portion of the Pancreas 497General Considerations 479 Liver & Biliary System 498Gastrointestinal Hormones 482Small Intestine 504Mouth & Esophagus 488Colon 508Stomach 491Section V References 512SECTION VI. CIRCULATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51527. Circulating Body Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515Introduction 515Red Blood Cells 532Blood 515 Blood Types 537Bone Marrow 515 Plasma 539White Blood Cells 516 Hemostasis 540Immunity 520Lymph 546Platelets 53128. Origin of the Heartbeat & the Electrical Activity of the Heart . . . . . . . . . . . . . . . . . . . . . . . . 547Introduction 547 Cardiac Arrhythmias 554Origin & Spread of Cardiac Electrocardiographic Findings in Other Cardiac Excitation 547& Systemic Diseases 561The Electrocardiogram 54929. The Heart as a Pump . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565Introduction 565Cardiac Output 570Mechanical Events of the Cardiac Cycle 56530. Dynamics of Blood & Lymph Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577Introduction 577 Capillary Circulation 590Functional Morphology 577Lymphatic Circulation & Interstitial FluidBiophysical Considerations 581 Volume 593Arterial & Arteriolar Circulation 587Venous Circulation 59531. Cardiovascular Regulatory Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597Introduction 597 Systemic Regulation by Hormones 600Local Regulation 597 Systemic Regulation by the Nervous System 602Substances Secreted by the Endothelium 598 9. viii / CONTENTS32. Circulation Through Special Regions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611Introduction 611 Brain Metabolism & OxygenCerebral Circulation 611 Requirements 619Anatomic Considerations 611Coronary Circulation 620Cerebrospinal Fluid 612Splanchnic Circulation 623The Blood-Brain Barrier 614Cutaneous Circulation 625Cerebral Blood Flow &Placental & Fetal Circulation 627 Its Regulation 61633. Cardiovascular Homeostasis in Health & Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630Introduction 630Inflammation & Wound Healing 635Compensations for Gravitational Shock 636 Effects 630Hypertension 641Exercise 632Heart Failure 643Section VI References 644SECTION VII. RESPIRATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64734. Pulmonary Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647Introduction 647 Gas Exchange in the Lungs 660Properties of Gases 647Pulmonary Circulation 661Anatomy of the Lungs 649 Other Functions of the Respiratory System 664Mechanics of Respiration 65035. Gas Transport Between the Lungs & the Tissues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666Introduction 666Carbon Dioxide Transport 669Oxygen Transport 66636. Regulation of Respiration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671Introduction 671 Chemical Control of Breathing 672Neural Control of Breathing 671Nonchemical Influences on Respiration 678Regulation of Respiratory Activity 67237. Respiratory Adjustments in Health & Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681Introduction 681 Hypercapnia & Hypocapnia 692Effects of Exercise 681Other Respiratory Abnormalities 692Hypoxia 683Diseases Affecting the Pulmonary Circulation 694Hypoxic Hypoxia 684Effects of Increased Barometric Pressure 694Other Forms of Hypoxia 690 Artificial Respiration 695Oxygen Treatment 691Section VII References 697SECTION VIII. FORMATION & EXCRETION OF URINE . . . . . . . . . . . . . . . . . . . . . . . . . . 69938. Renal Function & Micturition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699Introduction 699 Tubular Function 708Functional Anatomy 699 Water Excretion 713Renal Circulation 702Acidification of the UrineGlomerular Filtration 705& Bicarbonate Excretion 720 10. CONTENTS/ix Regulation of Na+ & Cl Excretion 723 Effects of Disordered Renal Function 725 Regulation of K+ Excretion 724The Bladder 726 Diuretics 72439. Regulation of Extracellular Fluid Composition & Volume. . . . . . . . . . . . . . . . . . . . . . . . . . . 729Introduction 729Defense of Specific Ionic Composition 730Defense of Tonicity 729 Defense of H+ Concentration 730Defense of Volume 729Section VIII References 738 Self-Study: Objectives, Essay Questions, & Multiple-Choice Questions (black edges) . . . . . . 739 Answers to Quantitative & Multiple-Choice Questions (black edges). . . . . . . . . . . . . . . . . . . 807 Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 811 General References 811 Some Standard Respiratory Symbols 821 Normal Values & the StatisticalEquivalents of Metric, United States, Evaluation of Data 811 & English Measures 821 Abbreviations & Symbols Commonly Greek Alphabet 822 Used in Physiology 814 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 823 Standard Atomic Weights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inside Front Cover Ranges of Normal Values in Human Whole Blood, Plasma, or Serum . . . . . . . . Inside Back Cover 11. This page intentionally left blank 12. PrefaceThis book is designed to provide a concise summary of mammalian and, particularly, of human physiology thatmedical students and others can use by itself or can supplement with readings in other texts, monographs, and re-views. Pertinent aspects of general and comparative physiology are also included. Summaries of relevant anatomicconsiderations will be found in each section, but this book is written primarily for those who have some knowledgeof anatomy, chemistry, and biochemistry. Examples from clinical medicine are given where pertinent to illustratephysiologic points. In many of the chapters, physicians desiring to use this book as a review will find short discus-sions of important symptoms produced by disordered function.Review of Medical Physiology also includes a self-study section to help students review for Board and other exami-nations and an appendix that contains general references, a discussion of statistical methods, a glossary of abbrevia-tions, acronyms, and symbols commonly used in physiology, and several useful tables. The index is comprehensiveand specifically designed for ease in locating important terms, topics, and concepts.In writing this book, the author has not been able to be complete and concise without also being dogmatic. I be-lieve, however, that the conclusions presented without detailed discussion of the experimental data on which theyare based are supported by the bulk of the current evidence. Much of this evidence can be found in the papers citedin the credit lines accompanying the illustrations. Further discussions of particular subjects and information on sub-jects not considered in detail can be found in the references listed at the end of each section. Information about ser-ial review publications that provide up-to-date discussion of various physiologic subjects is included in the note ongeneral references in the appendix. In the interest of brevity and clarity, I have in most instances omitted the namesof the many investigators whose work made possible the view of physiology presented here. This omission is in noway intended to slight their contributions, but including their names and specific references to original paperswould greatly increase the length of the book.In this twenty-second edition, as in previous editions, the entire book has been revised, with a view to eliminat-ing errors, incorporating suggestions of readers, updating concepts, and discarding material that is no longer rele-vant. In this way, the book has been kept concise while remaining as up-to-date and accurate as possible. Since thelast edition, research on the regulation of food intake has continued at a rapid pace, and this topic has been ex-panded in the current edition. So has consideration of mitochondria and molecular motors, with emphasis on theubiquity of the latter. Chapter 38 on renal function has been reorganized as well as updated. The section on estro-gen receptors has been revised in terms of the complexity of the receptor and the way this relates to tailor-madeestrogens used in the treatment of disease. Other topics on which there is new information include melanopsin,pheromones related to lactation, von Willebrand factor, and the complexity of connexons.The self-study section has been updated, with emphasis placed on physiology in relation to disease, in keepingwith the current trend in the United States Medical Licensing Examinations (USMLE).I am greatly indebted to the many individuals who helped with the preparation of this book. Those who were es-pecially helpful in the preparation of the twenty-second edition include Drs. Stephen McPhee, Dan Stites, DavidGardner, Igor Mitrovic, Michael Jobin, Krishna Rao, and Johannes Werzowa. Andrea Chase provided invaluablesecretarial assistance, and, as always, my wife made important contributions.Special thanks are due to Jim Ransom,who edited the first edition of this book over 42 years ago and now has come back to make helpful and worthwhilecomments on the two most recent editions. Many associates and friends provided unpublished illustrative materials,and numerous authors and publishers generously granted permission to reproduce illustrations from other booksand journals. I also thank all the students and others who took the time to write to me offering helpful criticismsand suggestions. Such comments are always welcome, and I solicit additional corrections and criticisms, which maybe addressed to me atDepartment of PhysiologyUniversity of CaliforniaSan Francisco, CA 94143-0444 USA Since this book was first published in 1963, the following translations have been published: Bulgarian, Chinese(2 independent translations), Czech (2 editions), French (2 independent translations), German (4 editions), Greek(2 editions), Hungarian, Indonesian (4 editions), Italian (9 editions), Japanese (17 editions), Korean, Malaysian,xi 13. xii / PREFACEPolish (2 editions), Portuguese (7 editions), Serbo-Croatian, Spanish (19 editions), Turkish (2 editions), andUkranian. Various foreign English language editions have been published, and the book has been recorded in Eng-lish on tape for the blind. The tape recording is available from Recording for the Blind, Inc., 20 Rozsel Road,Princeton, NJ 08540 USA. For computer users, the book is now available, along with several other titles in theLange Medical Books series, in STAT!-Ref, a searchable Electronic Medical Library (http://www.statref.com), fromTeton Data Systems, P.O. Box 4798 Jackson, WY 83001 USA. More information about this and other Lange andMcGraw-Hill books, including addresses of the publishers international offices, is available on McGraw-Hills website, www.AccessMedBooks.com. William F. Ganong, MDSan FranciscoMarch 2005 14. SECTION I Introduction The General & Cellular Basis of Medical Physiology 1INTRODUCTION closely resembles that of the primordial oceans in which, presumably, all life originated.In unicellular organisms, all vital processes occur in aIn animals with a closed vascular system, the ECF issingle cell. As the evolution of multicellular organisms divided into two components: the interstitial fluid andhas progressed, various cell groups have taken over par- the circulating blood plasma. The plasma and the cel-ticular functions. In humans and other vertebrate ani- lular elements of the blood, principally red blood cells,mals, the specialized cell groups include a gastrointesti- fill the vascular system, and together they constitute thenal system to digest and absorb food; a respiratorytotal blood volume. The interstitial fluid is that part ofsystem to take up O2 and eliminate CO2; a urinary sys- the ECF that is outside the vascular system, bathing thetem to remove wastes; a cardiovascular system to dis-cells. The special fluids lumped together as transcellulartribute food, O2, and the products of metabolism; a re-fluids are discussed below. About a third of the totalproductive system to perpetuate the species; and body water (TBW) is extracellular; the remaining twonervous and endocrine systems to coordinate and inte-thirds is intracellular (intracellular fluid).grate the functions of the other systems. This book isconcerned with the way these systems function and theway each contributes to the functions of the body as a Body Compositionwhole. In the average young adult male, 18% of the bodyThis chapter presents general concepts and princi- weight is protein and related substances, 7% is mineral,ples that are basic to the function of all the systems. It and 15% is fat. The remaining 60% is water. The dis-also includes a short review of fundamental aspects of tribution of this water is shown in Figure 11.cell physiology. Additional aspects of cellular and mole-The intracellular component of the body water ac-cular biology are considered in the relevant chapters on counts for about 40% of body weight and the extracel-the various organs.lular component for about 20%. Approximately 25% of the extracellular component is in the vascular systemGENERAL PRINCIPLES (plasma = 5% of body weight) and 75% outside theOrganization of the Body blood vessels (interstitial fluid = 15% of body weight). The total blood volume is about 8% of body weight.The cells that make up the bodies of all but the simplestmulticellular animals, both aquatic and terrestrial, exist Measurement of Body Fluid Volumesin an internal sea of extracellular fluid (ECF) en-closed within the integument of the animal. From thisIt is theoretically possible to measure the size of each offluid, the cells take up O2 and nutrients; into it, they the body fluid compartments by injecting substancesdischarge metabolic waste products. The ECF is morethat will stay in only one compartment and then calcu-dilute than present-day seawater, but its compositionlating the volume of fluid in which the test substance is 1 15. 2 / CHAPTER 1 Since 14,000 mL is the space in which the sucrose wasStomach Intestines distributed, it is also called the sucrose space.Volumes of distribution can be calculated for any Skinsubstance that can be injected into the body, providedBlood plasma:LungsKidneys the concentration in the body fluids and the amount 5% body weight removed by excretion and metabolism can be accurately Extra-measured.cellularAlthough the principle involved in such measure-fluid: ments is simple, a number of complicating factors must Interstitial fluid:20% body weight15% body weightbe considered. The material injected must be nontoxic, must mix evenly throughout the compartment being measured, and must have no effect of its own on the distribution of water or other substances in the body. In addition, either it must be unchanged by the body dur- ing the mixing period, or the amount changed must be known. The material also should be relatively easy to measure. Plasma Volume, Total Blood Volume, & Red Cell VolumeIntracellular fluid: Plasma volume has been measured by using dyes that40% body weightbecome bound to plasma proteinparticularly Evans blue (T-1824). Plasma volume can also be measured by injecting serum albumin labeled with radioactive io- dine. Suitable aliquots of the injected solution and plasma samples obtained after injection are counted in a scintillation counter. An average value is 3500 mL (5% of the body weight of a 70-kg man, assuming unit density). If one knows the plasma volume and the hematocrit (ie, the percentage of the blood volume that is made up of cells), the total blood volume can be calculated by multiplying the plasma volume by100Figure 11. Body fluid compartments. Arrows repre-sent fluid movement. Transcellular fluids, which consti-100 hematocrittute a very small percentage of total body fluids, are Example: The hematocrit is 38 and the plasma vol-not shown. ume 3500 mL. The total blood volume is100distributed (the volume of distribution of the injected3500 100 38 = 5645 mLmaterial). The volume of distribution is equal to theamount injected (minus any that has been removed The red cell volume (volume occupied by all thefrom the body by metabolism or excretion during thecirculating red cells in the body) can be determined bytime allowed for mixing) divided by the concentrationsubtracting the plasma volume from the total bloodof the substance in the sample. Example: 150 mg of su- volume. It may also be measured independently by in-crose is injected into a 70-kg man. The plasma sucrose jecting tagged red blood cells and, after mixing has oc-level after mixing is 0.01 mg/mL, and 10 mg has been curred, measuring the fraction of the red cells that isexcreted or metabolized during the mixing period. Thetagged. A commonly used tag is 51Cr, a radioactive iso-volume of distribution of the sucrose is tope of chromium that is attached to the cells by incu- bating them in a suitable chromium solution. Isotopes 150 mg 10 mgof iron and phosphorus (59Fe and 32P) and antigenic0.01 mg/mL = 14,000 mL tagging have also been employed. 16. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY / 3Extracellular Fluid Volume of water, the ratio of TBW to body weight varies with the amount of fat present. TBW is somewhat lower inThe ECF volume is difficult to measure because the women than men, and in both sexes, the values tend tolimits of this space are ill defined and because few sub-decrease with age (Table 11).stances mix rapidly in all parts of the space while re-maining exclusively extracellular. The lymph cannot beseparated from the ECF and is measured with it. Manysubstances enter the cerebrospinal fluid (CSF) slowlyUnits for Measuringbecause of the bloodbrain barrier (see Chapter 32). Concentration of SolutesEquilibration is slow with joint fluid and aqueous In considering the effects of various physiologically im-humor and with the ECF in relatively avascular tissues portant substances and the interactions between them,such as dense connective tissue, cartilage, and some the number of molecules, electric charges, or particlesparts of bone. Substances that distribute in ECF appearof a substance per unit volume of a particular bodyin glandular secretions and in the contents of the gas-fluid are often more meaningful than simply the weighttrointestinal tract. Because they are separated from the of the substance per unit volume. For this reason, con-rest of the ECF, these fluidsas well as CSF, the fluids centrations are frequently expressed in moles, equiva-in the eye, and a few other special fluidsare calledlents, or osmoles.transcellular fluids. Their volume is relatively small.Perhaps the most accurate measurement of ECF vol-ume is that obtained by using inulin, a polysaccharidewith a molecular weight of 5200. Mannitol and sucroseMoleshave also been used to measure ECF volume. A gener-A mole is the gram-molecular weight of a substance, ie,ally accepted value for ECF volume is 20% of the bodythe molecular weight of the substance in grams. Eachweight, or about 14 L in a 70-kg man (3.5 L = plasma;mole (mol) consists of approximately 6 1023 mole-10.5 L = interstitial fluid).cules. The millimole (mmol) is 1/1000 of a mole, and the micromole (mmol) is 1/1,000,000 of a mole. Thus, 1 mol of NaCl = 23 + 35.5 g = 58.5 g, and 1 mmol =Interstitial Fluid Volume58.5 mg. The mole is the standard unit for expressing the amount of substances in the SI unit system (see Ap-The interstitial fluid space cannot be measured directly,pendix).since it is difficult to sample interstitial fluid and since The molecular weight of a substance is the ratio ofsubstances that equilibrate in interstitial fluid also equi- the mass of one molecule of the substance to the masslibrate in plasma. The volume of the interstitial fluidof one twelfth the mass of an atom of carbon-12. Sincecan be calculated by subtracting the plasma volume molecular weight is a ratio, it is dimensionless. The dal-from the ECF volume. The ECF volume/intracellularton (Da) is a unit of mass equal to one twelfth the massfluid volume ratio is larger in infants and children thanof an atom of carbon-12, and 1000 Da = 1 kilodaltonit is in adults, but the absolute volume of ECF in chil- (kDa). The kilodalton, which is sometimes expresseddren is, of course, smaller than in adults. Therefore, de- simply as K, is a useful unit for expressing the molecu-hydration develops more rapidly and is frequently more lar mass of proteins. Thus, for example, one can speaksevere in children.of a 64-K protein or state that the molecular mass of the protein is 64,000 Da. However, since molecularIntracellular Fluid VolumeThe intracellular fluid volume cannot be measured di-rectly, but it can be calculated by subtracting the ECFTable 11. Total body water (as percentagevolume from the TBW. TBW can be measured by theof body weight) in relation to age and sex.same dilution principle used to measure the other bodyspaces. Deuterium oxide (D2O, heavy water) is mostAge (years) Male (%) Female (%)frequently used. D2O has slightly different propertiesfrom those of H2O, but in equilibration experiments 101859 57for measuring body water it gives accurate results. Tri-184061 51tium oxide (3H2O) and aminopyrine have also beenused for this purpose.406055 47 The water content of lean body tissue is constant atOver 6052 467172 mL/100 g of tissue, but since fat is relatively free 17. 4/ CHAPTER 1weight is a dimensionless ratio, it is incorrect to say that Buffersthe molecular weight of the protein is 64 kDa. Intracellular and extracellular pH are generally main- tained at very constant levels. For example, the pH ofEquivalentsthe ECF is 7.40, and in health, this value usually varies less than 0.05 pH unit. Body pH is stabilized by theThe concept of electrical equivalence is important in buffering capacity of the body fluids. A buffer is a sub-physiology because many of the important solutes in stance that has the ability to bind or release H+ in solu-the body are in the form of charged particles. One tion, thus keeping the pH of the solution relatively con-equivalent (eq) is 1 mol of an ionized substance divided stant despite the addition of considerable quantities ofby its valence. One mole of NaCl dissociates into 1 eq acid or base. One buffer in the body is carbonic acid.of Na+ and 1 eq of Cl. One equivalent of Na+ = 23 g; This acid is only partly dissociated into H+ and bicar-but 1 eq of Ca2+ = 40 g/2 = 20 g. The milliequivalent bonate: H2CO3 H+ + HCO3. If H+ is added to a so-(meq) is 1/1000 of 1 eq. lution of carbonic acid, the equilibrium shifts to the left Electrical equivalence is not necessarily the same as and most of the added H+ is removed from solution. Ifchemical equivalence. A gram equivalent is the weight OH is added, H+ and OH combine, taking H+ out ofof a substance that is chemically equivalent to 8.000 g solution. However, the decrease is countered by moreof oxygen. The normality (N) of a solution is the num- dissociation of H2CO3, and the decline in H+ concen-ber of gram equivalents in 1 liter. A 1 N solution of hy- tration is minimized. Other buffers include the blooddrochloric acid contains 1 + 35.5 g/L = 36.5 g/L. proteins and the proteins in cells. The quantitative as- pects of buffering and the respiratory and renal adjust-pH ments that operate with buffers to maintain a stable ECF pH of 7.40 are discussed in Chapter 39.The maintenance of a stable hydrogen ion concentra-tion in the body fluids is essential to life. The pH of asolution is the logarithm to the base 10 of the reciprocal Diffusionof the H+ concentration ([H+]), ie, the negative loga-rithm of the [H+]. The pH of water at 25 C, in whichDiffusion is the process by which a gas or a substance inH+ and OH ions are present in equal numbers, is solution expands, because of the motion of its particles,7.0 (Figure 12). For each pH unit less than 7.0, theto fill all of the available volume. The particles (mole-[H+] is increased tenfold; for each pH unit above 7.0, itcules or atoms) of a substance dissolved in a solvent areis decreased tenfold.in continuous random movement. A given particle is equally likely to move into or out of an area in which it is present in high concentration. However, since there are more particles in the area of high concentration, the total number of particles moving to areas of lower con- H+ concentration centration is greater; ie, there is a net flux of solute par- (mol/L)pH ticles from areas of high to areas of low concentration.10 11 The time required for equilibrium by diffusion is pro-10 22 portionate to the square of the diffusion distance. The ACIDIC10 33 magnitude of the diffusing tendency from one region to10 44 another is directly proportionate to the cross-sectional10 55 area across which diffusion is taking place and the con-10 66 For pure water, centration gradient, or chemical gradient, which is10 77[H+] = 107 mol/Lthe difference in concentration of the diffusing sub-10 8810 99 stance divided by the thickness of the boundary (Ficks law of diffusion). Thus, ALKALINE10 101010 1111 c10 1212 J = DA x10 131310 1414 where J is the net rate of diffusion, D is the diffusion coefficient, A is the area, and c/x is the concentra-Figure 12. pH. (Reproduced, with permission, from tion gradient. The minus sign indicates the direction ofAlberts B et al: Molecular Biology of the Cell, 4th ed. Gar- diffusion. When considering movement of moleculesland Science, 2002.) from a higher to a lower concentration, c/x is nega- 18. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY / 5tive, so multiplying by DA gives a positive value. The of solutions. In an ideal solution, osmotic pressure (P)permeabilities of the boundaries across which diffusion is related to temperature and volume in the same way asoccurs in the body vary, but diffusion is still a major the pressure of a gas:force affecting the distribution of water and solutes. nRT P= VOsmosisWhen a substance is dissolved in water, the concentra-where n is the number of particles, R is the gas con-tion of water molecules in the solution is less than that stant, T is the absolute temperature, and V is the vol-in pure water, since the addition of solute to water re-ume. If T is held constant, it is clear that the osmoticsults in a solution that occupies a greater volume than pressure is proportionate to the number of particles indoes the water alone. If the solution is placed on onesolution per unit volume of solution. For this reason,side of a membrane that is permeable to water but not the concentration of osmotically active particles is usu-to the solute, and an equal volume of water is placed onally expressed in osmoles. One osmole (osm) equals thethe other, water molecules diffuse down their concen- gram-molecular weight of a substance divided by thetration gradient into the solution (Figure 13). This number of freely moving particles that each moleculeprocessthe diffusion of solvent molecules into a re- liberates in solution. The milliosmole (mosm) isgion in which there is a higher concentration of a1/1000 of 1 osm.solute to which the membrane is impermeableisIf a solute is a nonionizing compound such as glu-called osmosis. It is an important factor in physiologiccose, the osmotic pressure is a function of the numberprocesses. The tendency for movement of solvent mole- of glucose molecules present. If the solute ionizes andcules to a region of greater solute concentration can beforms an ideal solution, each ion is an osmotically ac-prevented by applying pressure to the more concen-tive particle. For example, NaCl would dissociate intotrated solution. The pressure necessary to prevent sol- Na+ and Cl ions, so that each mole in solution wouldvent migration is the osmotic pressure of the solution. supply 2 osm. One mole of Na2SO4 would dissociateOsmotic pressure, like vapor pressure lowering, into Na+, Na+, and SO42, supplying 3 osm. However,freezing-point depression, and boiling-point elevation, the body fluids are not ideal solutions, and although thedepends on the number rather than the type of particles dissociation of strong electrolytes is complete, the num-in a solution; ie, it is a fundamental colligative property ber of particles free to exert an osmotic effect is reducedowing to interactions between the ions. Thus, it is actu-ally the effective concentration (activity) in the bodyfluids rather than the number of equivalents of an elec-Semipermeable trolyte in solution that determines its osmotic effect.membrane Pressure This is why, for example, 1 mmol of NaCl per liter inthe body fluids contributes somewhat less than 2 mosmof osmotically active particles per liter. The more con-centrated the solution, the greater the deviation froman ideal solution.The osmolal concentration of a substance in a fluidis measured by the degree to which it depresses thefreezing point, with 1 mol of an ideal solution depress-ing the freezing point 1.86 C. The number of millios-Figure 13. Diagrammatic representation of osmosis. moles per liter in a solution equals the freezing pointdepression divided by 0.00186. The osmolarity is theWater molecules are represented by small open circles,number of osmoles per liter of solution (eg, plasma),solute molecules by large solid circles. In the diagramwhereas the osmolality is the number of osmoles peron the left, water is placed on one side of a membranekilogram of solvent. Therefore, osmolarity is affected bypermeable to water but not to solute, and an equal vol- the volume of the various solutes in the solution andume of a solution of the solute is placed on the other. the temperature, while the osmolality is not. Osmoti-Water molecules move down their concentration gradi-cally active substances in the body are dissolved inent into the solution, and, as shown in the diagram onwater, and the density of water is 1, so osmolal concen-the right, the volume of the solution increases. As indi- trations can be expressed as osmoles per liter (osm/L) ofcated by the arrow on the right, the osmotic pressure iswater. In this book, osmolal (rather than osmolar) con-the pressure that would have to be applied to prevent centrations are considered, and osmolality is expressedthe movement of the water molecules.in milliosmoles per liter (of water). 19. 6 / CHAPTER 1Note that although a homogeneous solution con-and other fluid and electrolyte abnormalities. Hyperos-tains osmotically active particles and can be said to havemolality can cause coma (hyperosmolar coma; seean osmotic pressure, it can exert an osmotic pressure Chapter 19). Because of the predominant role of theonly when it is in contact with another solution across a major solutes and the deviation of plasma from an idealmembrane permeable to the solvent but not to thesolution, one can ordinarily approximate the plasma os-solute. molality within a few milliosmoles per liter by using thefollowing formula, in which the constants convert theclinical units to millimoles of solute per liter:Osmolal Concentration of Plasma: TonicityOsmolality = 2[Na+] + 0.055[Glucose] + 0.36[BUN]The freezing point of normal human plasma averages(mosm/L) (mEq/L) (mg/dL)(mg/dL)0.54 C, which corresponds to an osmolal concentra-tion in plasma of 290 mosm/L. This is equivalent to anBUN is the blood urea nitrogen. The formula is alsoosmotic pressure against pure water of 7.3 atm. The os- useful in calling attention to abnormally high concen-molality might be expected to be higher than this, be-trations of other solutes. An observed plasma osmolalitycause the sum of all the cation and anion equivalents in(measured by freezing-point depression) that greatly ex-plasma is over 300. It is not this high because plasma is ceeds the value predicted by this formula probably indi-not an ideal solution and ionic interactions reduce the cates the presence of a foreign substance such asnumber of particles free to exert an osmotic effect. Ex-ethanol, mannitol (sometimes injected to shrinkcept when there has been insufficient time after a sud- swollen cells osmotically), or poisons such as ethyleneden change in composition for equilibrium to occur, all glycol or methanol (components of antifreeze).fluid compartments of the body are in or nearly in os-motic equilibrium. The term tonicity is used to de- Regulation of Cell Volumescribe the osmolality of a solution relative to plasma.Solutions that have the same osmolality as plasma are Unlike plant cells, which have rigid walls, animal cellsaid to be isotonic; those with greater osmolality aremembranes are flexible. Therefore, animal cells swellhypertonic; and those with lesser osmolality are hypo-when exposed to extracellular hypotonicity and shrinktonic. All solutions that are initially isosmotic withwhen exposed to extracellular hypertonicity. However,plasma (ie, that have the same actual osmotic pressurecell swelling activates channels in the cell membraneor freezing-point depression as plasma) would remainthat permit increased efflux of K+, Cl, and small or-isotonic if it were not for the fact that some solutes dif- ganic solutes referred to collectively as organic os-fuse into cells and others are metabolized. Thus, a 0.9%molytes. Water follows these osmotically active parti-saline solution remains isotonic because there is no netcles out of the cell, and the cell volume returns tomovement of the osmotically active particles in the so- normal. Ion channels and other membrane transportlution into cells and the particles are not metabolized.proteins are discussed in detail in a later section of thisOn the other hand, a 5% glucose solution is isotonicchapter.when initially infused intravenously, but glucose is me-tabolized, so the net effect is that of infusing a hypo-Nonionic Diffusiontonic solution. Some weak acids and bases are quite soluble in cellIt is important to note the relative contributions of membranes in the undissociated form, whereas theythe various plasma components to the total osmolalcross membranes with difficulty in the ionic form.concentration of plasma. All but about 20 of theConsequently, if molecules of the undissociated sub-290 mosm in each liter of normal plasma are con-stance diffuse from one side of the membrane to thetributed by Na+ and its accompanying anions, princi-other and then dissociate, there is appreciable netpally Cl and HCO3. Other cations and anions make amovement of the undissociated substance from one siderelatively small contribution. Although the concentra-of the membrane to the other. This phenomenon,tion of the plasma proteins is large when expressed inwhich occurs in the gastrointestinal tract (see Chaptergrams per liter, they normally contribute less than 25) and kidneys (see Chapter 38), is called nonionic2 mosm/L because of their very high molecular weights.diffusion.The major nonelectrolytes of plasma are glucose andurea, which in the steady state are in equilibrium with Donnan Effectcells. Their contributions to osmolality are normallyabout 5 mosm/L each but can become quite large in When an ion on one side of a membrane cannot diffusehyperglycemia or uremia. The total plasma osmolalitythrough the membrane, the distribution of other ionsis important in assessing dehydration, overhydration, to which the membrane is permeable is affected in a 20. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY / 7predictable way. For example, the negative charge of a gradient for Cl exactly balanced by the oppositely di-nondiffusible anion hinders diffusion of the diffusiblerected electrical gradient, and the same holds true forcations and favors diffusion of the diffusible anions. K+. Third, since there are more proteins in plasma thanConsider the following situation,in interstitial fluid, there is a Donnan effect on ion movement across the capillary wall (see below). XYmK+K+ Forces Acting on IonsCl ClThe forces acting across the cell membrane on each ionProtcan be analyzed mathematically. Chloride ions are pre- sent in higher concentration in the ECF than in the cellin which the membrane (m) between compartments X interior, and they tend to diffuse along this concentra-and Y is impermeable to Prot but freely permeable totion gradient into the cell. The interior of the cell isK+ and Cl. Assume that the concentrations of the an-negative relative to the exterior, and chloride ions areions and of the cations on the two sides are initially pushed out of the cell along this electrical gradient. Anequal. Cl diffuses down its concentration gradientequilibrium is reached at which Cl influx and Cl ef-from Y to X, and some K+ moves with the negatively flux are equal. The membrane potential at which thischarged Cl because of its opposite charge. Thereforeequilibrium exists is the equilibrium potential. Its [K+X] > [K+Y] magnitude can be calculated from the Nernst equa- tion, as follows: Furthermore,RT [Cl ] ECl = In o[K+X] + [ClX] + [ProtX] > [K+Y] + [ClY] FZCl [Cli ]ie, more osmotically active particles are on side X than whereon side Y.Donnan and Gibbs showed that in the presence of a ECl = equilibrium potential for Clnondiffusible ion, the diffusible ions distribute them- R = gas constantselves so that at equilibrium, their concentration ratios T = absolute temperatureare equal:F = the faraday (number of coulombs per mole of charge) [K+X] [ClY] ZCl = valence of Cl (1)=[Clo] = Cl concentration outside the cell [K+Y] [ClX][Cli] = Cl concentration inside the cellCross-multiplying,Converting from the natural log to the base 10 log[K+X] [ClX] = [K+Y] [ClY]and replacing some of the constants with numerical val- ues, the equation becomesThis is the GibbsDonnan equation. It holds for anypair of cations and anions of the same valence.[Cli] ECl = 61.5 log at 37 CThe Donnan effect on the distribution of ions has [Clo]three effects in the body. First, because of proteins(Prot) in cells, there are more osmotically active parti- Note that in converting to the simplified expressioncles in cells than in interstitial fluid, and since animal the concentration ratio is reversed because the 1 va-cells have flexible walls, osmosis would make them lence of Cl has been removed from the expression.swell and eventually rupture if it were not for Na+K+ ECl, calculated from the values in Table 12, isadenosine triphosphatase (ATPase) pumping ions back70 mV, a value identical to the measured restingout of cells (see below). Thus, normal cell volume and membrane potential of 70 mV. Therefore, no forcespressure depend on Na+K+ ATPase. Second, becauseother than those represented by the chemical and elec-at equilibrium the distribution of permeant ions acrosstrical gradients need be invoked to explain the distribu-the membrane (m in the example used here) is asym- tion of Cl across the membrane.metric, an electrical difference exists across the mem-A similar equilibrium potential can be calculated forbrane whose magnitude can be determined by the K+ :Nernst equation (see below). In the example used here,side X will be negative relative to side Y. The charges RT [Ko+][Ko+] EK = In = 61.5 logat 37 Cline up along the membrane, with the concentrationFZK[Ki+] [Ki+] 21. 8 / CHAPTER 1Table 12. Concentration of some ions inside on the outside and anions on the inside. This conditionand outside mammalian spinal motor neurons.is maintained by Na+K+ ATPase, which pumps K+ back into the cell and keeps the intracellular concentra- Concentration tion of Na+ low. The Na+K+ pump is also electrogenic,(mmol/L of H2O)because it pumps three Na+ out of the cell for every two K+ it pumps in; thus, it also contributes a small amount Equilibrium to the membrane potential by itself. It should be em- InsideOutsidePotentialphasized that the number of ions responsible for theIon CellCell(mV) membrane potential is a minute fraction of the total number present and that the total concentrations ofNa+15.0 150.0+60 positive and negative ions are equal everywhere exceptK+ 150.0 5.5 90 along the membrane. Na+ influx does not compensate for the K+ efflux because the K+ channels (see below)Cl9.0 125.070 make the membrane more permeable to K+ than toResting membrane potential = 70 mVNa+.whereFUNCTIONAL MORPHOLOGY EK = equilibrium potential for K+ OF THE CELL ZK = valence of K+ (+1) Revolutionary advances in the understanding of cell[Ko+] = K+ concentration outside the cellstructure and function have been made through use of [Ki+] = K+ concentration inside the cellthe techniques of modern cellular and molecular biol- R, T, and F as aboveogy. Major advances have occurred in the study of em- bryology and development at the cellular level. Devel-In this case, the concentration gradient is outward and opmental biology and the details of cell biology arethe electrical gradient inward. In mammalian spinal beyond the scope of this book. However, a basic knowl-motor neurons, EK is 90 mV (Table 12). Since the edge of cell biology is essential to an understanding ofresting membrane potential is 70 mV, there is some- the organ systems in the body and the way they func-what more K+ in the neurons than can be accounted for tion.by the electrical and chemical gradients. The specialization of the cells in the various organsThe situation for Na+ is quite different from that for is very great, and no cell can be called typical of allK+ and Cl. The direction of the chemical gradient for cells in the body. However, a number of structures (or-Na+ is inward, to the area where it is in lesser concen- ganelles) are common to most cells. These structurestration, and the electrical gradient is in the same direc- are shown in Figure 14. Many of them can be isolatedtion. ENa is +60 mV (Table 12). Since neither EK nor by ultracentrifugation combined with other techniques.ENa is at the membrane potential, one would expect the When cells are homogenized and the resulting suspen-cell to gradually gain Na+ and lose K+ if only passive sion is centrifuged, the nuclei sediment first, followedelectrical and chemical forces were acting across the by the mitochondria. High-speed centrifugation thatmembrane. However, the intracellular concentration of generates forces of 100,000 times gravity or moreNa+ and K+ remain constant because there is active causes a fraction made up of granules called the micro-transport of Na+ out of the cell against its electrical and somes to sediment. This fraction includes organellesconcentration gradients, and this transport is coupled such as the ribosomes and peroxisomes.to active transport of K+ into the cell (see below).Genesis of the Membrane PotentialCell MembraneThe distribution of ions across the cell membrane andThe membrane that surrounds the cell is a remarkablethe nature of this membrane provide the explanationstructure. It is made up of lipids and proteins and isfor the membrane potential. The concentration gradi- semipermeable, allowing some substances to passent for K+ facilitates its movement out of the cell via K+ through it and excluding others. However, its perme-channels, but its electrical gradient is in the opposite ability can also be varied because it contains numerous(inward) direction. Consequently, an equilibrium isregulated ion channels and other transport proteins thatreached in which the tendency of K+ to move out of the can change the amounts of substances moving across it.cell is balanced by its tendency to move into the cell,It is generally referred to as the plasma membrane.and at that equilibrium there is a slight excess of cationsThe nucleus is also surrounded by a membrane of this 22. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY /9 Secretory granulesGolgiapparatus CentriolesRoughendoplasmicSmooth reticulum endoplasmic reticulumLysosomesNuclear envelope LipiddropletsMitochondrion Globular heads NucleolusFigure 14. Diagram showing a hypothetical cell in the center as seen with the light microscope. It is surroundedby various organelles. (After Bloom and Fawcett. Reproduced, with permission, from Junqueira LC, Carneiro J, Kelley RO:Basic Histology, 9th ed. McGraw-Hill, 1998.)type, and the organelles are surrounded by or made up prokaryotes (cells such as bacteria in which there is noof a membrane.nucleus), the membranes are relatively simple, but inAlthough the chemical structures of membranes and eukaryotes (cells containing nuclei), cell membranestheir properties vary considerably from one location to contain various glycosphingolipids, sphingomyelin, andanother, they have certain common features. They arecholesterol.generally about 7.5 nm (75 ) thick. The chemistry ofMany different proteins are embedded in the mem-proteins and lipids is discussed in Chapter 17. The brane. They exist as separate globular units and manymajor lipids are phospholipids such as phosphatidyl-pass through the membrane (integral proteins),choline and phosphatidylethanolamine. The shape ofwhereas others (peripheral proteins) stud the insidethe phospholipid molecule is roughly that of a clothes- and outside of the membrane (Figure 15). Thepin (Figure 15). The head end of the molecule con- amount of protein varies with the function of the mem-tains the phosphate portion and is relatively soluble inbrane but makes up on average 50% of the mass of thewater (polar, hydrophilic). The tails are relatively in-membrane; ie, there is about one protein molecule persoluble (nonpolar, hydrophobic). In the membrane, 50 of the much smaller phospholipid molecules. Thethe hydrophilic ends of the molecules are exposed toproteins in the membranes carry out many functions.the aqueous environment that bathes the exterior of the Some are cell adhesion molecules that anchor cells tocells and the aqueous cytoplasm; the hydrophobic ends their neighbors or to basal laminas. Some proteinsmeet in the water-poor interior of the membrane. In function as pumps, actively transporting ions across the 23. 10 / CHAPTER 1 16). Proteins may be myristolated, palmitoylated, or prenylated (ie, attached to geranylgeranyl or farnesyl groups). The protein structureand particularly the enzyme contentof biologic membranes varies not only from cell to cell but also within the same cell. For example, some of the enzymes embedded in cell membranes are different from those in mitochondrial membranes. In epithelial cells, the enzymes in the cell membrane on the mucosal surface differ from those in the cell mem- brane on the basal and lateral margins of the cells; ie, the cells are polarized. This is what makes transport across epithelia possible (see below). The membranes are dynamic structures, and their constituents are being constantly renewed at different rates. Some proteins are anchored to the cytoskeleton, but others move laterallyFigure 15. Biologic membrane. The phospholipidin the membrane. For example, receptors move in themolecules each have two fatty acid chains (wavy lines) membrane and aggregate at sites of endocytosis (seeattached to a phosphate head (open circle). Proteins are below).shown as irregular colored globules. Many are integral Underlying most cells is a thin, fuzzy layer plusproteins, which extend through the membrane, but pe- some fibrils that collectively make up the basementripheral proteins are attached to the inside (not shown) membrane or, more properly, the basal lamina. Theand outside of the membrane, sometimes by glyco- basal lamina and, more generally, the extracellular ma-sylphosphatidylinositol (GPI) anchors. trix are made up of many proteins that hold cells to- gether, regulate their development, and determine their growth. These include collagens, laminins (see below), fibronectin, tenascin, and proteoglycans.membrane. Other proteins function as carriers, trans-porting substances down electrochemical gradients by Mitochondriafacilitated diffusion. Still others are ion channels,which, when activated, permit the passage of ions into Over a billion years ago, aerobic bacteria were engulfedor out of the cell. The role of the pumps, carriers, and by eukaryotic cells and evolved into mitochondria,ion channels in transport across the cell membrane isproviding the eukaryotic cells with the ability to formdiscussed below. Proteins in another group function as the energy-rich compound ATP by oxidativereceptors that bind neurotransmitters and hormones,phosphenylation. Mitochondria perform other func-initiating physiologic changes inside the cell. Proteins tions, including a role in the regulation of apoptosisalso function as enzymes, catalyzing reactions at the(see below), but oxidative phosphorylation is the mostsurfaces of the membrane. In addition, some glycopro-crucial. Hundreds to thousands of mitochondria are inteins function in antibody processing and distinguish- each eukaryotic cell. In mammals, they are generallying self from nonself (see Chapter 27).sausage-shaped (Figure 14). Each has an outer mem-The uncharged, hydrophobic portions of the pro-brane, an intermembrane space, an inner membrane,teins are usually located in the interior of the mem-which is folded to form shelves (cristae), and a centralbrane, whereas the charged, hydrophilic portions are lo- matrix space. The enzyme complexes responsible forcated on the surfaces. Peripheral proteins are attachedoxidative phosphorylation are lined up on the cristaeto the surfaces of the membrane in various ways. One (Figure 17).common way is attachment to glycosylated forms ofConsistent with their origin from aerobic bacteria,phosphatidylinositol. Proteins held by these glyco-the mitochondria have their own genome. There issylphosphatidylinositol (GPI) anchors (Figure 15) much less DNA in the mitochondrial genome than ininclude enzymes such as alkaline phosphatase, variousthe nuclear genome (see below), and 99% of the pro-antigens, a number of cell adhesion molecules, and teins in the mitochondria are the products of nuclearthree proteins that combat cell lysis by complement (see genes, but mitochondrial DNA is responsible for cer-Chapter 27). Over 40 GPI-linked cell surface proteinstain key components of the pathway for oxidative phos-have now been described. Other proteins are lipidated, phorylation. Specifically, human mitochondrial DNAie, they have specific lipids attached to them (Figure is a double-stranded circular molecule containing 24. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY/ 11 Lipid membraneCytoplasmic or external face of membrane O N Gly Protein COOH N -Myristoyl H S-CysProteinNH2S -Palmitoyl O S-Cys Protein NH2Geranylgeranyl S-Cys Protein NH2 Farnesyl OCC CH2CC CHO OGPI anchor O C O P OInositol O C Protein(Glycosylphosphatidylinositol) H2O Hydrophobic domainHydrophilic domainFigure 16. Protein linkages to membrane lipids. Some are linked by their amino terminals, others by their car-boxyl terminals. Many are attached via glycosylated forms of phosphatidylinositol (GPI anchors). (Reproduced, withpermission, from Fuller GM, Shields D: Molecular Basis of Medical Cell Biology. McGraw-Hill, 1998.)16,569 base pairs (compared with over a billion in nu- Sperms contribute few, if any, mitochondria to theclear DNA). It codes for 13 protein subunits that arezygote, so the mitochondria come almost entirely fromassociated with proteins encoded by nuclear genes to the ovum and their inheritance is almost exclusivelyform four enzyme complexes plus two ribosomal andmaternal. Mitochondria have no effective DNA repair22 transfer RNAs (see below) that are needed for pro-system, and the mutation rate for mitochondrial DNAtein production by the intramitochondrial ribosomes. is over 10 times the rate for nuclear DNA. A largeThe enzyme complexes responsible for oxidative number of relatively rare diseases have now been tracedphosphorylation illustrate the interactions between theto mutations in mitochondrial DNA. These include forproducts of the mitochondrial genome and the nuclear the most part disorders of tissues with high metabolicgenome. For example, complex I, reduced nicotinamide rates in which energy production is defective as a resultadenine dinucleotide dehydrogenase (NADH), is made of abnormalities in the production of ATP.up of 7 protein subunits coded by mitochondrial DNAand 39 subunits coded by nuclear DNA. The origin ofLysosomesthe subunits in the other complexes is shown in Figure17. Complex II, succinate dehydrogenase-ubiquinoneIn the cytoplasm of the cell there are large, somewhatoxidoreductase, complex III, ubiquinone-cytochrome c irregular structures surrounded by membrane. The in-oxidoreductase, and complex IV, cytochrome c oxidase,terior of these structures, which are called lysosomes, isact with complex I coenzyme Q, and cytochrome c to more acidic than the rest of the cytoplasm, and externalconvert metabolites to CO2 and water. In the process,material such as endocytosed bacteria as well as worn-complexes I, III, and IV pump protons (H+) into theout cell components are digested in them. Some of theintermembrane space. The protons then flow through enzymes involved are listed in Table 13.complex V, ATP synthase, which generates ATP. ATPWhen a lysosomal enzyme is congenitally absent,synthase is unique in that part of it rotates in the gene- the lysosomes become engorged with the material thesis of ATP.enzyme normally degrades. This eventually leads to one 25. 12/ CHAPTER 1H+ H+H+ H+Intramemb space CoQ Cyt cInner mitomembraneASMatrix spaceADPATPComplexI II IIIIVVSubunits from7 0 1 3 2 mDNASubunits from 394 10 10 14 nDNAFigure 17. Formation of ATP by oxidative phosphorylation in mitochondria. As enzyme complexes I through IVconvert 2-carbon metabolic fragments to CO2 and H2O), protons (H+) are pumped into the intermembrane space.The proteins diffuse back to the matrix space via complex V, ATP synthase, in which ADP is converted to ATP. Theenzyme complexes are made up of subunits coded by mitochondrial DNA (mDNA) and nuclear DNA (nDNA), andthe figures document the contribution of each DNA to the complexes. See text for further details.of the lysosomal storage diseases. For example, - the peroxisome. The matrix contains more than 40 en-galactosidase A deficiency causes Fabrys disease, and -zymes, which operate in concert with enzymes outsidegalactocerebrosidase deficiency causes Gauchers dis-the peroxisome to catalyze a variety of anabolic andease. These diseases are rare, but they are serious andcatabolic reactions. Several years ago, a number of syn-can be fatal. Another example is the lysosomal storage thetic compounds were found to cause proliferation ofdisease called TaySachs disease, which causes mentalperoxisomes by acting on receptors in the nuclei ofretardation and blindness. cells. These receptors (PPARs) are members of the nu- clear receptor superfamily, which includes receptors forPeroxisomessteroid hormones, thyroid hormones, certain vitamins, and a number of other substances (see below). WhenPeroxisomes are found in the microsomal fraction ofactivated, they bind to DNA, producing changes in thecells. They are 0.5 mm in diameter and are surroundedproduction of mRNAs. Three PPAR receptors, ,by a membrane. This membrane contains a number ofand have been characterized. PPAR- and PPAR-peroxisome-specific proteins that are concerned with have received the most attention because PPAR-s aretransport of substances into and out of the matrix ofactivated by feeding and initiate increases in enzymes involved in energy storage, whereas PPAR-s are acti- vated by fasting and increase energy-producing enzymeTable 13. Some of the enzymes found activity. Thiazolidinediones are synthetic ligands forin lysosomes and the cell components PPAR-s and they increase sensitivity to insulin,that are their substrates. though their use in diabetes has been limited by their toxic side effects. Fibrates, which lower circulatingEnzyme Substrate triglycerides, are ligands for PPAR-s. Ribonuclease RNA Cytoskeleton DeoxyribonucleaseDNA All cells have a cytoskeleton, a system of fibers that not PhosphatasePhosphate esters only maintains the structure of the cell but also permits Glycosidases Complex carbohydrates; glyco-it to change shape and move. The cytoskeleton is madesides and polysaccharidesup primarily of microtubules, intermediate filaments, and microfilaments, along with proteins that anchor Arylsulfatases Sulfate esters them and tie them together. In addition, proteins and CollagenaseProteins organelles move along microtubules and microfilaments from one part of the cell to another propelled by molec- Cathepsins Proteins ular motors. 26. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY/ 13Microtubules (Figures 18 and 19) are long, hol- ble that organelles cannot move. Mitotic spindles can-low structures with 5-nm walls surrounding a cavity not form, and the cells die.15 nm in diameter. They are made up of two globular Intermediate filaments are 814 nm in diameterprotein subunits: - and -tubulin. A third subunit, - and are made up of various subunits. Some of these fila-tubulin, is associated with the production of micro-ments connect the nuclear membrane to the cell mem-tubules by the centrosomes (see below). The and brane. They form a flexible scaffolding for the cell andsubunits form heterodimers (Figure 19), which aggre- help it resist external pressure. In their absence, cellsgate to form long tubes made up of stacked rings, withrupture more easily; and when they are abnormal in hu-each ring usually containing 13 subunits. The tubules mans, blistering of the skin is common.also contain other proteins that facilitate their forma-Microfilaments (Figure 18) are long solid fiberstion. The assembly of microtubules is facilitated by46 nm in diameter that are made up of actin. Notwarmth and various other factors, and disassembly is fa-only is actin present in muscle (see Chapter 3), but itcilitated by cold and other factors. The end where as-and its mRNA are present in all types of cells. It is thesembly predominates is called the + end, and the endmost abundant protein in mammalian cells, sometimeswhere disassembly predominates is the end. Both accounting for as much as 15% of the total protein inprocesses occur simultaneously in vitro.the cell. Its structure is highly conserved; for example,Because of their constant assembly and disassembly, 88% of the amino acid sequences in yeast and rabbitmicrotubules are a dynamic portion of the cell skeleton.actin are identical. Actin filaments polymerize and de-They provide the tracks along with several differentpoidymerize in vivo, and it is not uncommon to findmolecular motors for transport vesicles, organelles suchpolymerization occurring at one end of the filamentas secretory granules, and mitochondria from one part while depolymerization is occurring at the other end.of the cell to another. They also form the spindle, The fibers attach to various parts of the cytoskeletonwhich moves the chromosomes in mitosis. Micro-(Figure 110). They reach to the tips of the microvillitubules can transport in both directions. on the epithelial cells of the intestinal mucosa. They areMicrotubule assembly is prevented by colchicine also abundant in the lamellipodia that cells put outand vinblastine. The anticancer drug paclitaxel when they crawl along surfaces. The actin filaments in-(Taxol) binds to microtubules and makes them so sta-teract with integrin receptors and form focal adhesion MF MTFigure 18. Left: Electron micrograph of the cytoplasm of a fibroblast, showing microfilaments (MF) and micro-tubules (MT). (Reproduced, with permission, from Junqueira LC, Carneiro J: Basic Histology, 10th ed. McGraw-Hill, 2003.)Right: Distribution of microtubules in fibroblasts. The cells are treated with a fluorescently labeled antibody to tubu-lin, making microtubules visible as the light-colored structures. (Reproduced, with permission, from Connolly J et al:Immunofluorescent staining of cytoplasmic and spindle microtubules in mouse fibroblasts with antibody to protein.Proc Natl Acad Sci U S A 1977;74:2437.) 27. 14/ CHAPTER 1 -Tubulin24 nm-Tubulin 5 nm () End(+) EndCross sectionLongitudinal sectionTubulin heterodimersFigure 19. Microtuble, showing assembly by addition of - and -tubulin dimers and disassembly by removal ofthese units. (Modified from Borison WF, Boupaep EL: Medical Physiology, Saunders, 2003).complexes, which serve as points of traction with the and then bends its neck while the other head swingssurface over which the cell pulls itself. In addition,forward and binds, producing almost continuoussome molecular motors use microfilaments as tracks. movement. Some kinesins are associated with mitosisand meiosis. Other kinesins perform different func-tions, including, in some instances, moving cargo to theMolecular Motors end of microtubules.The molecular motors that move proteins, organelles,Dyneins have two heads, with their neck piecesand other cell parts (their cargo) to all parts of the cell embedded in a complex of proteins (Figure 111). Cy-are 100500-kDa ATPases. They attach to their cargo toplasmic dynein has a function like that of conven-and their heads bind to microtubules or actin polymers. tional kinesin, except that it moves particles and mem-Hydrolysis of ATP in their heads causes the molecules branes to the end of the microtubules. Axonemalto move. There are two types of molecular motors: dynein oscillates and is responsible for the beating ofthose producing motion along microtubules and those flagella and cilia (see below). The multiple forms ofproducing motion along actin (Table 14). Examplesmyosin in the body are divided into 18 classes. Theare shown in Figure 111, but each type is a member ofheads of myosin molecules bind to actin and producea superfamily, with many forms throughout the animalmotion by bending their neck regions (myosin II) orkingdom.walking along microfilaments, one head after the other The conventional form of kinesin is a double-(myosin V). In these ways, they perform functions asheaded molecule that moves its cargo toward the + endsdiverse as contraction of muscle (see Chapter 3) andof microtubules. One head binds to the microtubulecell migration.Glycophorin C Anion exchangerMembraneActin (Band 3)Ankyrin 4.1Adducin4.1 4.2 Actin chain chainSpectrin 4.9Tropomyosin TropomodulinFigure 110. Membrane-cytoskeleton attachments in the red blood cell, showing the various proteins that anchoractin microfilaments to the membrane. Some are identified by numbers (4.1, 4.2, 4.9), whereas others have receivednames. (Reproduced, with permission, from Luna EJ, Hitt AL: Cytoskeleton-plasma membrane interactions. Science1992;258:955.) 28. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY / 15Table 14. Examples of molecular motors.cell division. In multinucleate cells, a centrosome isnear each nucleus. Microtubule-based Conventional kinesin Cilia DyneinsCells have various types of projections. True cilia aredynein-driven motile processes that are used by unicel- Actin-basedlular organisms to propel themselves through the water Myosins IVand by multicellular organisms to propel mucus andother substances over the surface of various epithelia.They resemble centrioles in having an array of ninetubular structures in their walls, but they have in addi-Centrosomes tion a pair of microtubules in the center, and two ratherthan three microtubules are present in each of the nineNear the nucleus in the cytoplasm of eukaryotic animalcircumferential structures. The basal granule, on thecells is a centrosome. The centrosome is made up of other hand, is the structure to which each cilium is an-two centrioles and surrounding amorphous pericentri-chored. It has nine circumferential triplets, like a centri-olar material. The centrioles are short cylinders ole, and there is evidence that basal granules and centri-arranged so that they are at right angles to each other.oles are interconvertible.Microtubules in groups of three run longitudinally inthe walls of each centriole (Figure 14). Nine of these Cell Adhesion Moleculestriplets are spaced at regular intervals around the cir-cumference. Cells are attached to the basal lamina and to each otherThe centrosomes are microtubule-organizing cen- by cell adhesion molecules (CAMs) that are promi-ters (MTOCs) that contain -tubulin. The micro- nent parts of the intercellular connections describedtubules grow out of this -tubulin in the pericentriolarbelow. These adhesion proteins have attracted great at-material. When a cell divides, the centrosomes dupli- tention in recent years because they are important incate themselves, and the pairs move apart to the polesembryonic development and formation of the nervousof the mitotic spindle, where they monitor the steps in system and other tissues; in holding tissues together in CargoLightchains 4 nm Conventional kinesin 80 nmCytoplasmic dynein Cargo-binding domainHead 1 Head 2 Head 2Head 1 ADP ADP ATP Actin Myosin VFigure 111. Three examples of molecular motors. Conventional kinesin is shown attached to cargo, in this case amembrane-bound organelle. The way that myosin V walks along a microtuble is also shown. Note that the headsof the motors hydrolyze ATP and use the energy to produce motion. 29. 16/ CHAPTER 1adults; in inflammation and wound healing; and in themetastasis of tumors. Many pass through the cell mem-brane and are anchored to the cytoskeleton inside thecell. Some bind to like molecules on other cells (ho-mophilic binding), whereas others bind to other mole-Tightcules (heterophilic binding). Many bind to laminins, a junctionfamily of large cross-shaped molecules with multiple re- (zonula occludens)ceptor domains in the extracellular matrix.Nomenclature in the CAM field is somewhatZonulachaotic, partly because the field is growing so rapidly adherensand partly because of the extensive use of acronyms, asin other areas of modern biology. However, the CAMs Desmosomescan be divided into four broad families: (1) integrins,heterodimers that bind to various receptors; (2) adhe-sion molecules of the IgG superfamily of immuno-globulins; (3) cadherins, Ca2+-dependent moleculesthat mediate cell-to-cell adhesion by homophilic reac-Gaptions; and (4) selectins, which have lectin-like domainsjunctionsthat bind carbohydrates. The functions of CAMs ingranulocytes and platelets are described in Chapter 27,and their roles in inflammation and wound healing arediscussed in Chapter 33.HemidesmosomeThe CAMs not only fasten cells to their neighbors,but they also transmit signals into and out of the cell.Figure 112. Intercellular junctions in the mucosa ofCells that lose their contact with the extracellular ma-the small intestine. Focal adhesions are not shown intrix via integrins have a higher rate of apoptosis (see detail.below) than anchored cells, and interactions betweenintegrins and the cytoskeleton are involved in cellmovement.these junctions are a significant part of overall ion andIntercellular Connections solute flux. In addition, tight junctions prevent themovement of proteins in the plane of the membrane,Two types of junctions form between the cells thathelping to maintain the different distribution of trans-make up tissues: junctions that fasten the cells to one porters and channels in the apical and basolateral cellanother and to surrounding tissues, and junctions thatmembranes that make transport across epithelia possi-permit transfer of ions and other molecules from oneble (see above and Chapters 25 and 38).cell to another. The types of junctions that tie cells to-In epithelial cells, each zonula adherens is usually agether and endow tissues with strength and stability in-continuous structure on the basal side of the zonula oc-clude the tight junction, which is also known as thecludens, and it is a major site of attachment for intracel-zonula occludens. The desmosome and zonula ad-lular microfilaments. It contains cadherins.herens (Figure 112) hold cells together, and the Desmosomes are patches characterized by apposedhemidesmosome and focal adhesion attach cells tothickenings of the membranes of two adjacent cells. At-their basal laminas. Tight junctions between epithelial tached to the thickened area in each cell are intermedi-cells are also essential for transport of ions across epithe- ate filaments, some running parallel to the membranelia. The junction by which molecules are transferred is and others radiating away from it. Between the twothe gap junction. membrane thickenings. The intercellular space containsTight junctions characteristically surround the api-filamentous material that includes cadherins and the ex-cal margins of the cells in epithelia such as the intestinaltracellular portions of several other transmembrane pro-mucosa, the walls of the renal tubules, and the choroid teins.plexus. They are made up of ridgeshalf from one cell Hemidesmosomes look like half-desmosomes thatand half from the otherwhich adhere so strongly at attach cells to the underlying basal lamina and are con-cell junctions that they almost obliterate the space be-nected intracellularly to intermediate filaments. How-tween the cells. They permit the passage of some ions ever, they contain integrins rather than cadherins. Focaland solute, and the degree of this leakiness varies. Ex-adhesions also attach cells to their basal laminas. Astracellular fluxes of ions and solute across epithelia at noted above, they are labile structures associated with 30. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY/ 17actin filaments inside the cell, and they play an impor- the particular connexin subunits that make up connex-tant role in cell movement.ons determine their permeability and selectivity.Gap JunctionsNucleus & Related StructuresAt gap junctions, the intercellular space narrows from A nucleus is present in all eukaryotic cells that divide. If25 nm to 3 nm, and units called connexons in the mem-a cell is cut in half, the anucleate portion eventually diesbrane of each cell are lined up with one another (Figure without dividing. The nucleus is made up in large part113). Each connexon is made up of six protein sub-of the chromosomes, the structures in the nucleus thatunits called connexins. They surround a channel that,carry a complete blueprint for all the heritable specieswhen lined up with the channel in the correspondingand individual characteristics of the animal. Except inconnexon in the adjacent cell, permits substances to germ cells, the chromosomes occur in pairs, one origi-pass between the cells without entering the ECF. The nally from each parent (see Figure 232). Each chro-diameter of the channel is normally about 2 nm, whichmosome is made up of a giant molecule of deoxyri-permits the passage of ions, sugars, amino acids, andbonucleic acid (DNA). The DNA strand is about 2 mother solutes with molecular weights up to about 1000. long, but it can fit in the nucleus because at intervals itGap junctions thus permit the rapid propagation of is wrapped around a core of histone proteins to form aelectrical activity from cell to cell (see Chapter 4) andnucleosome. There are about 25 million nucleosomesthe exchange of various chemical messengers. However,in each nucleus. Thus, the structure of the chromo-the gap junction channels are not simply passive, non- somes has been likened to a string of beads. The beadsspecific conduits. At least 20 different genes code forare the nucleosomes, and the linker DNA betweenconnexins in humans, and mutations in these genes canthem is the string. The whole complex of DNA andlead to diseases that are highly selective in terms of the proteins is called chromatin. During cell division, thetissues involved and the type of condition produced. coiling around histones is loosened, probably by acety-For instance, X-linked CharcotMarieTooth disease lation of the histones, and pairs of chromosomes be-is a peripheral neuropathy associated with mutation of come visible, but between cell divisions only clumps ofone particular connexin gene. Experiments in mice in chromatin can be discerned in the nucleus. The ulti-which particular connexins are deleted by gene manipu- mate units of heredity are the genes on the chromo-lation or replaced with different connexins confirm that somes (see below). Each gene is a portion of the DNA molecule. During normal cell division by mitosis, the chro- mosomes duplicate themselves and then divide in such a way that each daughter cell receives a full complement (diploid number) of chromosomes. During their finalPresynapticmaturation, germ cells undergo a division in which halfmembrane 4 nmthe chromosomes go to each daughter cell (see ChapterGap23). This reduction division (meiosis) is actually a two-(extracellular 2 nmstage process, but the important consideration is that asspace) a result of it, mature sperms and ova contain half thePostsynaptic 5 nmnormal number (the haploid number) of chromo-membrane somes. When a sperm and ovum unite, the resultant cell (zygote) has a full diploid complement of chromo-8 nm somes, one-h