Physiology - An Illustrated Review E-Book

Roger TannerThies

• Herausgeber: Thieme Medical Publishers
• Kategorie: Fachliteratur
• Sprache: Englisch

Veröffentlichungsjahr: 2011

Beschreibung

Introducing Thieme's illustrated Review Series
Concise course reviews that also test your knowledge for the USMLE!

Thieme's illustrated Review Series serves an important dual purpose for medical students—both concise course review and high-yield USMLE® test preparation. Covering all the basic science subjects that you will take in medical school and that will be found on the USMLE® Step 1, the series features unparalleled color illustrations, a streamlined format, and hundreds of print and online study questions and answers—all designed to increase your mastery of the topics, promote classroom success, and boost your confidence for the exam!

Physiology—An Illustrated Review helps you master the important physiologic facts and concepts, organized by organ system, and teaches you how to apply that knowledge for classroom and USMLE® success. This indispensable review book includes:

• Hundreds of beautifully detailed, fully labeled color illustrations that clarify each concept
• A succinct, bullet-point format that focuses on must-master classroom and exam information
• Handy sidebars that integrate key content across the basic science curriculum and demonstrate clinical correlations
• Clear tables that summarize topics and provide easy-to-study review
• 200 USMLE®-style and factual self-testing questions—with explanatory answers—that give you intensive practice in each area
• An additional 200 interactive questions and answers—for a total of 400—are available online via the scratch-off code in your book, offering immediate feedback and quickly identifying areas for further study

This print book includes complimentary access to a digital copy on https://medone.thieme.com.

Publisher's Note: Products purchased from Third Party sellers are not guaranteed by the publisher for quality, authenticity, or access to any online entitlements included with the product.

Leseprobe

PhysiologyAn Illustrated Review

Roger TannerThies, PhD

Professor Emeritus of PhysiologyThe University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma

Thieme

New York • Stuttgart

Thieme Medical Publishers, Inc.333 Seventh Ave.New York, NY 10001

Vice President and Editorial Director, Educational Products: Anne T. VinnicombeDevelopmental Editor: Julie O’MearaProduction Editor: Megan ConwaySenior Vice President, International Sales and Marketing: Cornelia SchulzeDirector of Sales: Ross LumpkinChief Financial Officer: Sarah VanderbiltPresident: Brian D. ScanlanCompositor: Manila Typesetting CompanyPrinter: Transcontinental Interglobe Printing Inc.

Illustrations: By Atelier Gay + Rothenburger (Sternsfels, Germany) from Stefan Silbernagl and Agamemnon Despopoulos: Color Atlas of Physiology, sixth edition, © Thieme 2009, and other books in the Thieme Flexibook series, except as noted.

Library of Congress Cataloging-in-Publication Data

TannerThies, Roger.

Physiology: an illustrated review/Roger TannerThies.

p.; cm. – (Thieme illustrated review series)

Includes index.

Summary: “Physiology—An Illustrated Review helps you master important physiologic facts and concepts and teaches you how to apply that knowledge successfully on course exams and in daily practice. This indispensable review book includes 200 spectacular, full-color illustrations depicting cardiologic, cellular, and renal function. It also includes all the regular series features, including 400 print and online review questions and explanatory answers”—Provided by publisher.

ISBN 978-1-60406-202-1 (pbk.)

 1. Human physiology—Atlases. 2. Human physiology—Examinations, questions, etc. I. Title. II. Series: Thieme illustrated review series

[DNLM: 1. Physiological Phenomena—Atlases. 2. Physiological Phenomena–Examination Questions. QT 18.2]

QP40.T36 2012

612—dc23

2011027808

Copyright ©2012 by Thieme Medical Publishers, Inc. This book, including all parts thereof, is legally protected by copyright. Any use, exploitation, or commercialization outside the narrow limits set by copyright legislation without the publisher’s consent is illegal and liable to prosecution. This applies in particular to photostat reproduction, copying, mimeographing or duplication of any kind, translating, preparation of microfilms, and electronic data processing and storage.

Important note: Medical knowledge is ever-changing. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may be required. The authors and editors of the material herein have consulted sources believed to be reliable in their efforts to provide information that is complete and in accord with the standards accepted at the time of publication. However, in view of the possibility of human error by the authors, editors, or publisher of the work herein or changes in medical knowledge, neither the authors, editors, nor publisher, nor any other party who has been involved in the preparation of this work, warrants that the information contained herein is in every respect accurate or complete, and they are not responsible for any errors or omissions or for the results obtained from use of such information. Readers are encouraged to confirm the information contained herein with other sources. For example, 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 publication 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.

Some of the product names, patents, and registered designs referred to in this book are in fact registered trademarks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a representation by the publisher that it is in the public domain.

Printed in Canada

5 4 3 2 1

ISBN 978-1-60406-202-1

Your Illustrated Review Series book is a two-part package that will be invaluable for your course and exams. In addition to the wealth of illustrations and information in this book, you also get access to 400 review questions online at WinkingSkull.com. These questions (200 from the book plus 200 more) – both factual and clinical-case-based multiple choice – all have answer explanations for right and wrong answers. Test yourself and get immediate feedback, quickly identifying areas of mastery or for further study.

After completing a short form to verify your e-book purchase, you will be provided with the instructions and access codes necessary to retrieve access to the review questions.

Please visit http://www.thieme.com/bonuscontent to get started today!

This book is dedicated to my family:   My wife, Nancy   My sons, Eric and David   My stepchildren, Curtis and Christina

Contents

Preface

I Cell Physiology

1 The Cell Membrane

2 Neurotransmission

3 Muscle Cell Physiology

Questions & Answers

II Neurophysiology

4 Autonomic Nervous System

5 Sensory Systems

6 Motor Systems

7 Higher Cortical Functions

Questions & Answers

III Cardiovascular Physiology

8 Electrophysiology of the Heart

9 The Heart as a Pump

10 The Circulation

11 Response of the Cardiovascular System to Gravity, Exercise, and Hemorrhage

Questions & Answers

IV Respiratory Physiology

12 Ventilation and Pulmonary Blood Flow

13 Gas Exchange and Transport

14 Control of Respiration

Questions & Answers

V Renal Physiology and Acid–base Balance

15 Renal Anatomy, Body Fluids, Glomerular Filtration, and Renal Clearance

16 Renal Tubular Transport

17 Regulation of Water Balance and the Concentration and Dilution of Urine

18 Acid–base Balance

Questions & Answers

VI Gastrointestinal Physiology

19 Structure and Regulation of the Gastrointestinal Tract

20 Gastrointestinal Motility

21 Gastrointestinal Secretion

22 Digestion and Absorption

Questions & Answers

VII Endocrine Physiology

23 General Principles of Endocrine Physiology

24 The Pituitary Gland

25 Thyroid Hormones

26 Calcium Metabolism

27 Adrenal Hormones

28 Endocrine Pancreas

Questions & Answers

VIII Reproductive Physiology

29 Sexual Differentiation, Puberty, and Male and Female Reproduction

Questions & Answers

Index

Preface

Understanding human physiology, the function of the body, from subcellular processes to those of the whole organism, is essential for any health professional. Health depends upon the proper functioning of all body systems. When there is a malfunction, our bodies have many methods of self-correction, but they also benefit from interventions by skilled health professionals. In order to intervene successfully, the health professional has to correctly diagnose the malfunction, provide the appropriate treatment, and monitor and recognize when function returns to normal. This chain of events is all dependent on an understanding of physiology.

Our understanding of physiology has developed over the last century and a half due to the efforts of thousands of medical scientists. The French physiologist, Claude Bernard, summarized his understanding of the functions of the body with a book entitled, “The Basis of Experimental Medicine” 150 years ago. His best known concept is that of the internal environment and its relative constancy. All cells in the body are bathed in a dilute salt solution similar to that of sea water eons ago. Our bodies regulate the composition of this solution to maintain the viability of all our cells. One part of physiology is the study of how the body regulates the composition of this solution. About 100 years ago, Walter Cannon, MD, coined the term “homeostasis” to describe this constancy. Such control is not static, but requires energy to maintain the steady state of the bathing solution. About 50 years ago, Arthur Guyton, MD, the great physiology teacher, and others applied engineering control systems theory to physiological processes. Negative feedback control is one concept they applied to physiological systems. So physiological understanding continues to grow.

There have been many breakthroughs in our understanding of physiology in recent years. We can now describe many of the mechanisms by which the brain and psychological states influence functions of other organs and body systems. Molecular genetics has discovered the genetic defects that lead to many pathophysiological processes, and ways of treating such defects have been devised. Satellite cells that were originally described in skeletal muscle tissue 40 years ago have now been seen in most tissues and provide a means of regeneration of tissues and possibly organs. As physiological understanding continues to expand, medical science will find treatments to maintain longer and better human life.

Physiology—An Illustrated Review covers the facts of physiology and integrates the concepts that you must master for success in the classroom and for the USMLE. It provides a concise study aid for physiology courses. It can also be used as a succinct source of key knowledge for daily clinical practice.

This book is in a streamlined bullet-point format and includes hundreds of full-color illustrations that demonstrate physiologic processes.

Sidebars connect physiologic concepts in the text with normal function (orange), fundamental biochemical, genetic, and embryologic processes (green), and disease and treatment (blue).

For self-testing, the text includes both factual and USMLE-style questions. All of the questions are accompanied by explanatory answers. The 200 questions and answers in the text are supplemented by an additional 200 questions and answers online at WinkingSkull. com via the scratch-off code in the book. The questions provide intensive practice, offer immediate feedback, and will allow you to quickly identify areas for further study.

As you use this book, please send comments or suggestions you have for improvement to [email protected].

Acknowledgements

This book grew out of a previous review book, Oklahoma Notes Physiology, which went through four editions between 1987 and 1995. That book was written by all faculty in the Department of Physiology, namely Kirk W. Barron, Robert C. Beesley, Siribhinya Benyajati, Robert W. Blair, Kenneth J. Dormer, Jay P. Farber, Robert D. Foreman, Kennon M. Garrett, Stephen S. Hull, Jr., Philip A. McHale, Y. S. Reddy, Rex D. Stith, and Roger Thies. Some years later the author adapted Oklahoma Notes Physiology into outline form and matched the text to 2,000 questions from Biotest Physiology. At that time Stephen S. Hull, Jr., made a major contribution by rewriting the chapters on cardiovascular and respiratory physiology. Norman Levine, Carl L. Thompson, and Norman Weisbrodt reviewed individual chapters.

The following faculty and students reviewed various chapters of this book and updated the information: John P. Pooler (Emory University School of Medicine), Henry Edinger (New Jersey Medical School), Ronaldo P. Ferraris (New Jersey Medical School), Paul Greenman (Nova Southeastern University), Norman Levine (Nova Southeastern University), Nicholas Lufti (Nova Southeastern University), Michael Markus (Wright State University), Kenneth D. Mitchell (Tulane University School of Medicine), James Michael Olcese (Florida State University College of Medicine), William H. Percy (Sanford School of Medicine at the University of South Dakota), Dexter Speck (University of Kentucky College of Medicine), Carl Thompson (New York Medical College), Gabi N. Waite (Indiana University School of Medicine), Douglas Wangensteen (University of Minnesota), Anthony Cheng (Feinberg School of Medicine, Northwestern University), Catherine Howard (Tulane University School of Medicine), Chris Lee (Harvard Medical School), Joshua Lennon (Albany Medical College), and Kelly Wright (John H. Stroger, Jr., Hospital of Cook County).

The author appreciates the helpful contributions of the Thieme editorial staff to this book. Cathrin Weinstein, MD, provided initial guidance. Anne Vinnicombe improved the organization and presentation in many ways. The first developmental editor, Rebecca McTavish, contributed to this book by organizing the material, requesting more explanations, and generally giving life to the words. The second developmental editor, Julie O’Meara, made the presentation more focused, systematic, and clinically relevant. Avalon Garcia improved the questions and explanations. Megan Conway guided this book to its final form.

Roger TannerThiesJefferson City, MO

1 The Cell Membrane

1.1 Structure of the Cell Membrane

Membrane Components

Lipid Bilayer

Cell membranes are made up of amphipathic phospholipids with polar (hydrophilic) heads and apolar (hydrophobic) fatty acid tails (Fig. 1.1). Amphipathic molecules tend to arrange themselves to minimize the contact of hydrophobic portions with water. This causes the spontaneous formation of a lipid bilayer. Cholesterol molecules in the lipid bilayer affect membrane fluidity.

Proteins

Integral membrane proteins are embedded in the lipid bilayer and have contact with both the extracellular and intracellular fluid. Most have components that span the bilayer multiple times. Peripheral membrane proteins are associated with either the phospholipid (hydrophilic) heads or other embedded proteins.

Carbohydrates

Oligosaccharide residues combine with lipids and proteins on the outer cell membrane surface to form glycolipids and glycoproteins.

– Glycolipids and glycoproteins both contribute to structural stability of cell membranes.

– Glycoproteins are also important for cell recognition and immune response.

Intercellular Connections

Tight Junctions

Tight junctions are attachments between epithelial cells.

– True “tight” junctions prevent the movement of dissolved molecules and water from one side to the other.

– “Leaky” tight junctions act as a pathway for solutes and water to cross epithelial cell layers.

Gap Junctions

Gap junctions are channels between cells that permit intercellular communication.

– Small molecules (ions, adenosine triphosphate [ATP], cyclic adenosine monophosphate [cAMP], etc.) can pass through gap junctions.

– Gap junctions electrically couple cells, so they act together as a functional syncytium (e.g., in the heart and smooth muscles of the gut).

1.2 Transport across Membranes

Selective transport of substances across cell membranes allows cells to regulate their internal content and to carry out crucial functions such as secretion and absorption, which are controlled by neural and hormonal activity.

Fig. 1.1 Structure of the cell membrane.

The cell membrane consists of a phospholipid bilayer. Each phospholipid molecule has a glycerol head (hydrophilic) and two fatty acid tails (hydrophobic). These hydrophobic tails are arranged so that they face each other in the bilayer. Integral proteins and cholesterol are embedded within the bilayer. Other proteins may lie peripherally. Carbohydrate moieties may bind to lipids and proteins on the extracellular surface of the membrane, forming glycolipids and glycoproteins.

Free Diffusion

Free diffusion is the migration of molecules from a region of higher concentration to one of lower concentration as a result of random motion (Fig. 1.2).

– Free diffusion does not require external energy and is therefore passive.

– Example: Oxygen (O2) and carbon dioxide (CO2) move across cell membranes down their concentration gradients by diffusion.

Fick’s Law

Fick’s first law of diffusion states that the net flow of a substance (J) is proportional to the membrane permeability (P), the concentration gradient (ΔC), and the available area for diffusion (A):

where

Membrane permeability.Membrane permeability is a variable in Fick’s law and is increased by

– ↑ lipid solubility of the solute

– ↓ membrane thickness

– ↓ size of the solute

Lipid-soluble, small, nonionized substances are most permeable (Fig. 1.3).

Fig. 1.2 Passive transport: free diffusion and uniport.

Free diffusion occurs when a substance moves across a membrane down its electrochemical gradient. When this process requires a transport (carrier) protein, it is known as uniport or facilitated diffusion. It is a conformational change in the transport protein that permits this membrane transport. Both of these forms of membrane transport are passive because they do not require energy.

Fig. 1.3 Permeability of membranes.

Small apolar and polar uncharged molecules can diffuse freely through cell membranes. Large molecules and charged molecules cannot diffuse freely and must be transported to cross a membrane.

Carrier-mediated Transport

Carriers are integral membrane proteins that transport substances that are hydrophilic or too large to cross the membrane by simple diffusion. They also permit faster transport of lipid-soluble substances than simple diffusion. Carrier proteins possess the following characteristics:

– Selectivity: Most carriers exhibit a preference for just one or a small class of solutes.

– Competition for binding sites: Structurally related compounds can compete for binding sites and inhibit the binding of the related solute to the carrier protein; for example, glucose and galactose compete with each other for absorption into enterocytes by Na+-dependent cotransport (SGLT1).

– Saturation of carrier proteins: The rate of carrier-mediated transport may show saturation at high solute concentrations, as the number of carrier proteins is finite, and the cycling of carrier proteins is limited.

Uniport

Uniport (formerly called facilitated diffusion) is a carrier-mediated transport mechanism that moves solutes down their electrochemical gradients (Fig. 1.2).

– It does not use metabolic energy and is therefore passive.

– Example: In the transport of glucose into red blood cells, L-glucose cannot enter red blood cells by simple diffusion. D-glucose enters via a protein glucose transporter that transports other sugars poorly. D-glucose transport saturates when all the transporters are being used.

Primary Active Transport

Primary active transport is a carrier-mediated transport mechanism that moves molecules against their electrochemical gradients (Fig. 1.4).

– It requires metabolic energy and uses ATP as the direct energy source.

– Example: Na+−K+ ATPase (carrier protein) pumps Na+ out of the cell and K+ into the cell against their concentration gradients. It maintains a low intracellular [Na+] and high intracellular [K+] ratio. Three Na+ ions are transported out of the cell for every two K+ ions that are transported into the cell (Fig. 1.5).

– Example: Ca2+−ATPase transports Ca2+ back into Ca2+ stores in a muscle cell and out of a muscle cell after the influx of Ca2+ triggers muscle contractions.

H+−K+ ATPase (the proton pump)

H+−K+ ATPase is an integral transmembrane protein that is present in gastric parietal cells. It functions to actively transport H+ into the lumen of the stomach, against its electrochemical gradient, in exchange for K+ (one H+ is exchanged for one K+). The energy required to drive this exchange is derived from the hydrolysis of ATP. In the lumen, Cl− and H+ combine to form gastric acid. Proton pump inhibitors (e.g., omeprazole) inhibit the H+−K+ ATPase pump, thus inhibiting gastric acid secretion into the lumen of the stomach. These drugs are used to treat peptic ulcers and gastroesophageal reflux disease (GERD).

Digoxin

Digoxin is a cardiac glycoside that was once one of the first-line agents used in the treatment of heart failure. Its use is now reserved for cases when symptoms are not fully treated by standard therapies or in cases of severe heart failure while standard therapies are initiated. The therapeutic and toxic effects of digoxin are attributable to inhibition of Na+−K+ ATPase (the digitalis receptor) located on the outside of the myocardial cell membrane. When the pump is inhibited, Na+ accumulates intracellularly. The decreased Na+ gradient that results from this affects Na+−Ca2+ exchange, and Ca2+ accumulates intracellularly. Consequently, more Ca2+ (stored in the sarcoplasmic reticulum) is available for release and interaction with the contractile proteins in these cells during the excitation–contraction coupling process. At therapeutic doses of digoxin, there is an increase in contractile force. Toxicity to digoxin also relates to inhibition of Na+−K+ ATPase. Inhibition of the Na+−K+ pump affects the K+ gradient; this may lead to a significant reduction of intracellular K+, predisposing the heart to arrhythmias. Likewise, high levels of Ca2+ intracellularly may contribute to serious arrhythmias.

Fig. 1.4 Active transport.

Active transport occurs when a substance is transported across a membrane against its electrochemical gradient by transport proteins. This process requires energy in the form of adenosine triphosphate (ATP), therefore it is active. The transport protein (an ATPase) binds the substance on one side of the membrane, and ATP-dependent phosphorylation causes a conformational change that releases it on the other side of the membrane.

Secondary Active Transport

Secondary active transport is a carrier-mediated transport mechanism that uses the downhill movement of one substance to move another substance uphill. The flow of one species down its electrochemical gradient powers the actively transported species against its electrochemical gradient (Fig. 1.6). The electrochemical gradient for Na+ is usually maintained by the Na+−K+ ATPase pump.

– Symporters carry the substrate and cosubstrate in the same direction.

– Example: In Na+−glucose cotransport in the small intestine and kidney, Na+ transported into cells brings glucose with it.

– Antiporters carry the substrate and cosubstrate in opposite directions.

– Example: HCO3−−Cl− countertransport at red blood cell membranes.

– Example: 3Na+−Ca2+ countertransport at cardiac muscle cell membranes.

Fig. 1.5 Na+−K+ ATPase.

The Na+−K+ ATPase (Na+−K+ pump) is present in all cell membranes. It consists of two α subunits and two β subunits. The α subunits are phosphorylated, causing a conformational change that allows them to form the ion transport pathway. During one transport cycle, three Na+ ions are pumped out of the cell, and two K+ ions are pumped into the cell by the Na+−K+ ATPase using one molecule of adenosine triphosphate (ATP). Both Na+ and K+ ions are transported against their concentration gradients. (ADP, adenosine diphosphate)

Fig. 1.6 Secondary active transport.

Secondary active transport occurs when uphill transport of a substance via a carrier protein (e.g., sodium–glucose transport type 2 [SGLT2]) is coupled with the downhill transport of an ion (Na+ in this example) (1). In this case, the electrochemical Na+ gradient into the cell (maintained by Na+−K+ ATPase) provides the driving force for the cotransport of glucose into the cell. The SGLT2 is an example of a symporter, as Na+ and glucose are transported in the same direction. Examples 2 and 3 also illustrate symport. Antiport occurs when the compound and driving ions are transported in opposite directions. For example, when an electrochemical Na+ gradient drives H+ in the opposite direction (4).

Transport of Water across Membranes

Osmosis

Osmosis is the net diffusion of water across a semipermeable (permeable to water but not solutes) membrane. The osmolarity of a solution is the concentration of osmotically active particles in the solution. The net movement of water across a semipermeable membrane is due to the concentration differences of the nonpenetrating solutes. Water diffuses from a low osmolarity solution (high water concentration, low solute concentration) to a high osmolarity solution (low water concentration, high solute concentration) in attempting to achieve equal water concentrations on both sides of the membrane (Fig. 1.7).

Fig. 1.7 Water output and intake from the cell by osmosis.

In a hypertonic environment, there is a higher concentration of solutes outside the cell than inside, so water moves out of the cell by osmosis. In a hypotonic environment, there is a higher concentration of solutes inside the cell, so extracellular water moves into the cell by osmosis.

Osmotic Pressure. The osmotic pressure of a solution is the theoretical hydrostatic pressure that would be required to just prevent the osmotic flow of water across a semipermeable membrane. Numerically, it is simply a constant multiplied by the osmolality.

The flow of water through a membrane is expressed by the van’t Hoff equation:

where

Reflection Coefficient. The reflection coefficient is a number between 0 and 1 that describes the ability of a membrane to prevent diffusion of a solute relative to water.

– If the reflection coefficient is 1, the solute is completely impermeable and will not pass through the membrane. Serum albumin has a reflection coefficient that is close to 1. This explains why albumin is retained in the vascular compartment and exerts an osmotic effect.

– If it is 0, the solute will pass through the membrane as easily as water and will not exert any osmotic effect (i.e., it will not cause water to flow).

1.3 Receptors and Signal Transduction

Types of Receptor

Ligand-gated Ion Channels

Ligand-gated ion channels are specialized membrane pores made up of multisubunit proteins. Binding of ligands (e.g., hormones or neurotransmitters) to these receptors opens or closes the pores, thus changing the permeability of the membrane to Na+, K+, Cl−, or other ions (Fig. 1.8).

Fig. 1.8 Ligand-gated ion channel.

An example of a ligand-gated ion channel is the nicotinic receptor of the motor end plate. When two acetylcholine (ACh) molecules bind to this receptor simultaneously (at the α subunits), the inner pore opens; Na+ then enters the cell, and K+ leaves the cell. This causes membrane depolarization.

− Examples: Nicotinic receptor for acetylcholine (see Fig. 2.2), the glutamate receptor, and the gamma-aminobutyric acid type A (GABAA) receptor

G-Protein Coupled Receptors. G proteins facilitate signal transduction that is initiated by ligand-receptor binding and culminates in a cellular response. The mechanisms of G-protein signal transduction are discussed on page 9.

Voltage-dependent Ion Channels

Voltage-dependent ion channels open or close in response to changes in the membrane potential.

– Example: Depolarization opens the activation gate of Na+ channels, allowing Na+ to flow into cells.

Calcium channel blockers

Calcium channel blockers (e.g., verapamil and nifedipine) inhibit Ca2+ entry into cells via voltage-dependent ion channels. In smooth muscle cells, this produces arterial vasodilation, which leads to reduced coronary artery spasm, decreased blood pressure, and reduced cardiac work. In cardiac muscle cells, these agents inhibit cardiac functions, causing decreased heart rate, atrioventricular conduction, and contractility. Nifedipine acts predominantly on smooth muscle cells to produce vasodilation and has almost no effect on cardiac function at therapeutic doses. Verapamil acts on both smooth muscle cells and heart muscle cells.

Enzyme-linked Membrane Receptors

When a ligand binds to this receptor, it causes an enzyme to become “switched on” intracellularly. This enzyme then catalyzes the formation of other signal proteins that ultimately lead to the drug’s effect.

– Example: Insulin “switches on” the tyrosine kinase activity of the insulin receptor to affect glucose uptake into cells (Fig. 1.9).

Fig. 1.9 Enzyme-linked membrane receptor.

Insulin binding to the receptor causes the enzyme, tyrosine kinase, to phosphorylate tyrosine residues in proteins. These proteins can then signal other proteins to be formed, thus exerting the physiological effect.

Fig. 1.10 Intracellular receptor.

Lipophilic substances, such as steroid hormones and thyroid hormones, can diffuse through the cell membrane and interact with receptors in the cytoplasm or nucleus. The hormone-receptor complex then alters gene transcription causing proteins that exert the physiological effect to be made. The hormone-receptor complex interacts with DNA in pairs that may be identical (homodimeric) or nonidentical (heterodimeric).

Intracellular Receptors

Lipid-soluble substances diffuse through cell membranes and bind either to receptors in the cellular cytosol or in the nucleus. Gene expression is altered, and protein synthesis is either increased or decreased, which causes the cellular response (Fig. 1.10).

– Examples: Steroid hormones, calcitriol, and thyroxine

G-Protein Coupled Receptors and Signal Transduction

Heterotrimeric G proteins couple to membrane receptors (e.g., α-adrenergic receptors). When the receptor binds a ligand, this causes the α-subunit of the G protein to split from the β and γ subunits. The now free subunits then interact with other proteins in the membrane that may produce second messengers (Fig. 1.11). These second messengers are cAMP, diacylglycerol (DAG), and inositol 1,4,5-triphosphate (IP3).

– Gs proteins activate adenylate cyclase.

– Gi proteins inhibit adenylate cyclase.

– Gq proteins activate phospholipase C, which then activates DAG and IP3.

Fig. 1.11 Signal transduction by G proteins.

A substance binding to a G-protein coupled receptor alters its conformation and causes the α subunit of the attached G protein to exchange guanosine diphosphate (GDP) for guanosine triphosphate (GTP) (1). The G protein then separates from the receptor and dissociates into an α subunit and a βγ subunit. In the case illustrated, the α subunit activates adenylate cyclase, which promotes cyclic adenosine monophosphate (cAMP) production (2). The cAMP then acts as a second messenger, activating protein kinase A, which, in turn, activates further proteins (see Fig. 1.12). The intrinsic GTPase activity of the α subunit hydrolyzes bound GTP to GDP, thereby terminating the effect of the G protein. (ATP, adenosine triphosphate; PPi, diphosphate)

When G proteins are activated, guanosine triphosphate (GTP) replaces guanosine diphosphate (GDP) on the α subunit. Following activation of G proteins, GTP is rapidly degraded to inactive GDP by the activity of the α-subunit GTPase.

Second Messenger Systems

Adenylate Cyclase System. Gs-activating substances bind to a receptor that activates Gs, which, in turn, stimulates adenylate cyclase to convert ATP to cAMP, which then activates protein kinase A. This phosphorylates proteins, resulting in the physiologic response. Following its activation, cAMP is degraded to 5′ AMP by phosphodiesterase (Fig. 1.12).

Gi-activating substances bind to a receptor that activates Gi, which inhibits adenylate cyclase (↓cAMP). Therefore, protein kinase A is not activated, and proteins are not phosphorylated.

DAG and IP3 System. The amplifier enzyme phospholipase C produces the second messengers IP3 and DAG from a single precursor (Fig. 1.13).

Hydrophilic IP3 diffuses from the membrane to organelles containing Ca2+ and releases it. The Ca2+ released can then cause physiologic effects in the following ways:

– Interaction with the cAMP system

– Activation of protein kinase C (with DAG) leading to the phosphorylation of proteins

– Binding to calmodulin with the resultant complex mediating further effects, for example, production of nitric oxide (Fig. 1.14)

Lipophilic DAG has two functions:

– Activation of protein kinase C (this process is Ca2+ dependent)

– Formation of arachidonic acid (an eicosanoid precursor) following its degradation by DAG lipase.

Phosphodiesterase inhibitors

Phosphodiesterase inhibitors inhibit the degradation of cAMP and cyclic guanosine monophosphate (cGMP). Drugs that specifically inhibit phosphodiesterase type 5 (e.g., sildenafil citrate [Viagra]) cause prolonged vasodilation of penile arteries and are therefore used to treat erectile dys-function. Phosphodiesterase inhibitors type 3 (e.g., milrinone and inamrinone) increase cAMP levels in cardiac cells. This causes an increase in intracellular Ca2+, resulting in increased heart rate and force of contraction (positive chronotropic and inotropic effects). They also cause vasodilation of blood vessels. These agents are used as adjuvants in heart failure therapy. Side effects of phosphodiesterase inhibitors include headache and cutaneous flushing.

Fig. 1.12 Cyclic AMP.

Adenylate cyclase synthesizes cAMP by cleaving diphosphate (PPi) from ATP. Adenylate cyclase is regulated by G proteins (Gs and Gi), which are controlled by substances attaching to G-protein coupled 7-helix receptors. The cAMP activates protein kinase A (PKA), which then phosphorylates proteins, including enzymes, transcription factors, and ion channels.

Fig. 1.13 Diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3).

Binding of a molecule to a G protein activates phospholipase C, which, in turn, activates DAG and IP3. Both DAG and IP3 act to phosphorylate effector proteins. DAG also forms eicosanoids. Ca2+ exerts further effects by forming a complex with calmodulin. (ECF, extracellular fluid; PIP2, phosphadidylinositol-4, 5-biphosphonate; cGMP, cyclic guanosine monophosphate)

Fig. 1.14 Nitric oxide (NO) as a transmitter substance.

Ca2+−calmodulin complex activates nitric oxide synthase, which catalyzes the formation of NO from arginine. NO is then able to diffuse to other cells, where it activates guanylate cyclase, which converts GTP to cyclic guanosine monophosphate (cGMP). The cGMP activates protein kinase G, which, in turn, decreases the intracellular Ca2+ concentration by blocking the IP3 receptors on Ca2+ stores. This culminates in vasodilation. (ECF, extracellular fluid; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; PIP2, phosphadidylinositol-4,5-biphosphonate, PLC, phospholipase C)

1.4 Membrane Potentials

Equilibrium Potential

Ion movement or flux is controlled by both concentration gradients and electrical gradients. If these gradients are equal but opposite in direction for a particular ion, then its total electrochemical potential is zero, and there is no net current flow. This is electrochemical equilibrium.

The equilibrium potential is the membrane potential for an ion that would exactly oppose the tendency of an ion to move down its concentration gradient. It is calculated using the Nernst equation:

where

– Example: The equilibrium potential for K+ is calculated as follows:

Resting Membrane Potential

The resting membrane potential (RMP) is the normal potential difference across a membrane (in millivolts). It is established as a result of the difference in concentration of permeable ions across the membrane (Fig. 1.15) as each of these ions tries to reach its equilibrium potential.

– Skeletal muscle cell membranes at rest are 30 times more permeable to K+ than Na+, so the RMP of −90 mV approaches the equilibrium potential for K+ of −96 mV.

Fig. 1.15 Resting potential.

The resting membrane potential results from the uneven distribution of positively and negatively charged ions inside and outside the cell. The Na+−K+ ATPase pump establishes concentration differences by pumping three Na+ ions out of the cell and two K+ ions into the cell. Some K+ ions flow back down this concentration gradient and leave the cell via K+ channels. The protein anions that predominate inside the cell cannot follow them. The result is a slight excess of positively charged ions outside the cell, with a slight excess of anions inside the cell. The force of attraction between positive and negative ions creates the resting membrane potential (RMP).

– Neural cells are only 6 times as permeable, so they have RMPs of −70 mV. Cl− distributes passively at the potential determined by primarily K+ and secondarily by Na+.

– The Na+−K+ ATPase pump is responsible for generating the concentration differences needed to cross the membrane.

– The RMP is stored energy (a battery) whose brief discharge generates an action potential that can transmit a signal rapidly for a long distance through the body.

1.5 Action Potentials

Table 1.2 defines terms that must be understood when considering action potentials.

Action Potential Events

Depolarization

Depolarization due to a graded potential reduces the RMP approximately −15 mV. Some fast voltage-gated Na+ channels are activated and open, allowing some Na+ to enter the cell (Fig. 1.16).

When the depolarization threshold is reached, the action potential is initiated. Inward current causes the membrane potential difference to move rapidly toward the Na+ equilibrium potential of +55 mV. During this rising phase of depolarization, the relative conductance of the membrane to Na+ increases to ~50 times the conductance of K+. In the overshoot phase of an action potential, the membrane potential passes zero and is reversed (positive).

Repolarization

Na+ channels close spontaneously within a millisecond after opening. This process is called inactivation. The conductance of K+ also increases. The decrease of Na+ conductance relative to K+ causes the membrane to repolarize back toward the RMP, which facilitates the repolarization.

The electrochemical gradient for Na+ is usually maintained by the Na+−K+ ATPase pump.

Hyperpolarization

The membrane hyperpolarizes briefly at the end of the action potential as it passes the RMP. This is due to the greater than normal conductance of K+ during repolarization. The RMP is reestablished as Na+ and K+ conductances return to their resting states.

Fig. 1.16 Action potential and ion conductivity.

Following the binding of a neurotransmitter to an inotropic receptor on the postsynaptic membrane, the following steps occur that culminate in an action potential: (1) Voltage-gated Na+ channels open, and due to their high equilibrium potential, Na+ ions flow into the cell, causing depolarization. (2) The Na+ channels immediately close again, so the influx of positive charges is very brief. (3) Voltage-dependent K+ channels open, and K+ flows out of the cell. This results in repolarization of the membrane. (4) This briefly leads to the potential falling below resting membrane potential (RMP), and the membrane is hyperpolarized. The K+ channels then close, and if there are gap junctions, the neuron is ready for restimulation. The Na+−K+ATPase (labeled in the membrane) operates continuously to maintain the concentration gradient for Na+ and K+.

Absolute Refractory Period

The absolute refractory period is the period when the membrane cannot be stimulated to produce a second action potential regardless of the stimulus strength. It is the duration of the action potential and is due to the inactivation of the majority of membrane Na+ channels.

Relative Refractory Period

The relative refractory period occurs after the absolute refractory period. During this time, a significantly larger depolarization stimulus (inward flow) can initiate an additional action potential. This is due to a prolonged increase in K+ conductance during this time, which opposes depolarization as the membrane is farther from threshold.

Accommodation

Accommodation is a slight increase in threshold in response to prolonged subthreshold stimulation.

– It is caused by a continuous activation and inactivation of some Na+ channels and K+ channels, so fewer Na+ channels are available for activation. It may occur in smooth muscle cells of the gut.

Propagation of Action Potentials

When an action potential depolarizes one portion of a membrane, local currents (Na+ influx) depolarize adjacent areas of the membrane, bringing them to threshold. Thus, the action potentials are propagated.

Conduction Velocity

The conduction velocity of action potentials moving along nerve axons is increased by

– ↑ axon radius: Thicker axons have lower intracellular resistance to local current flow, so conduction velocity is faster.

– Myelination: Conduction velocity is greatly increased in myelinated neurons due to the insulating effects of the myelin and because myelin allows for saltatory conduction. In saltatory conduction, Na+ currents can only flow at the nodes of Ranvier, where the myelin sheath is absent, so the action potential “jumps” from node to node (Fig. 1.17). This significantly increases conduction velocity and requires less energy.

Fig. 1.17 Continuous (1a, 1b) and saltatory (2) propagation of action potentials.

(1a) Na+ enters the nerve fiber, causing depolarization of the adjacent membrane. (1b) Na+ then enters the adjacent membrane. The region of depolarization moves. (2) Myelin insulation forces current to flow to the next node of Ranvier, causing depolarization there. Na+ then enters at the next node of Ranvier, ~1 mm along the nerve fiber.

2 Neurotransmission

Propagated action potentials carry information through axons over long distances, but they do not transfer electrical impulses directly to other neurons, glands, or muscle cells. Communication between most nerve cells is accomplished via neurotransmitter molecules released at synapses.

2.1 Neurotransmitters

Acetylcholine

Synthesis. Acetylcholine is synthesized from acetyl coenzyme A (CoA) and choline by the enzyme choline acetyltransferase in the presynaptic terminal. The uptake of choline is the rate-limiting step.

Coenzyme A

Pantothenic acid (vitamin B5) is a precursor of CoA. CoA participates in fatty acid synthesis and oxidation, as well as the oxidation of pyruvate in the citric acid cycle. A molecule of CoA that has an acetyl group is referred to as acetyl CoA. Acetate, which is derived from acetyl CoA, combines with choline to form the neurotransmitter a cetylcholine.

Degradation. Breakdown is rapid via acetylcholinesterase to produce acetate and choline. Acetylcholinesterase is located on neuronal membranes, muscle cell membranes, and red blood cells. Pseudocholinesterases (nonspecific) and butyrylcholinesterases, which are more widely distributed, can also hydrolyze acetylcholine.

Release. Acetylcholine is the neurotransmitter released from the following neurons (see also page 35 and Fig. 4.1):

– Pre- and postganglionic parasympathetic neurons

– Preganglionic sympathetic neurons

– Postganglionic sympathetic neurons that innervate sweat glands

– Motoneurons at the neuromuscular junction

Norepinephrine

Synthesis. Norepinephrine is synthesized from the precursor amino acid tyrosine by hydroxylation to dihydroxyphenylalanine (dopa) in the postganglionic neuron. Dopa is decarboxylated to dopamine, which is oxidized to norepinephrine and packaged in vesicles.

Degradation. Termination of action is primarily by reuptake (60–90%) into nerve terminals. Secondary degradation is by monoamine oxidase (MAO) and catechol O-methyltransferase (COMT).

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors (MAOIs, e.g., isocarboxazid and phenelzine) inhibit both forms of the enzyme monoamine oxidase (MAO-A and MAO-B). In doing so, they prevent the degradation of norepinephrine, epinephrine, and dopamine. These drugs are used in the treatment of depression when tricyclic antidepressants are in effective. It takes 2 to 3 weeks for the desired effects of these drugs to occur.

Hypertensive crisis with monoamine oxidase inhibitors

Hypertensive crisis may occur within hours of ingestion of tyramine-containing foods, including cheese, certain meats (liver and fermented or cured meats), cured or pickled fish, overripe fruits and vegetables, Chianti wine, and some beers. Hypertensive crisis is characterized by headache, palpitation, neck stiffness or soreness, nausea, vomiting, sweating (sometimes with fever or cold, clammy skin), photophobia, tachycardia or bradycardia, constricting chest pain, and dilated pupils. Potentially fatal intracranial bleeding may result from this crisis. Patients should avoid tyramine-containing foods while taking MAOIs and for 2 weeks after treatment with MAOIs is discontinued to avoid precipitating this condition, but if it does occur, then treatment is with intravenous phentolamine.

Release. Norepinephrine is the main neurotransmitter released from postganglionic sympathetic neurons. It is also released in small quantities from the adrenal medulla along with epinephrine.

Epinephrine

Synthesis. Epinephrine is produced from norepinephrine in the adrenal medulla via the enzyme phenylethanolamine N-methyltransferase.

Degradation. Epinephrine is degraded by MAO and COMT.

Release. Epinephrine is released from the adrenal medulla along with some norepinephrine.

Dopamine

Synthesis. Dopamine is a precursor in the formation of both norepinephrine and epinephrine.

Degradation. Dopamine is degraded by MAO and COMT.

Release. Dopamine acts as a neurotransmitter in the central nervous system (CNS), especially in the extrapyramidal motor system.

Glutamate

Synthesis. Glutamate is synthesized from glucose via glutamine.

Degradation. Glutamate is converted back to glutamine, and its action is terminated by reuptake into cells in the CNS.

Release. Glutamate is the principal excitatory amino acid neurotransmitter in the CNS.

Gamma-Aminobutyric Acid

Synthesis. Glucose is the principal in vivo source of gamma-aminobutyric acid (GABA). There is a GABA “shunt” of the Krebs cycle that results in the conversion of glutamate into GABA by the action of the enzyme glutamate decarboxylase.

Degradation. GABA is converted back to glutamate, then to glutamine. Its action is terminated by reuptake into cells in the CNS.

Release. GABA is the principal inhibitory amino acid neurotransmitter in the CNS.

Serotonin

Synthesis. Serotonin (5-hydroxytryptamine [5-HT]) is synthesized from tryptophan by tryptophan hydroxylase.

Degradation. Serotonin is degraded by MAO.

Release. Serotonin acts as a neurotransmitter in the CNS.

Carcinoid syndrome

Carcinoid tumors are neuroendocrine tumors of the gastrointestinal (GI) tract, urogenital tract, or pulmonary bronchioles. They can contain and secrete numerous autocoids, including prostaglandins and serotonin, causing symptoms such as flushing and diarrhea. Cardiac disease due to fibrosis of the endocardium and valves, along with asthma-like symptoms, are also common. Flushing may be precipitated by stress, alcohol, certain foods, or drugs, particularly serotonin-specific reuptake inhibitors (SSRIs), so these should be avoided. Heart failure, wheezing, and diarrhea are treated, respectively, with diuretics, a bronchodilator, and an antidiarrheal agent, such as loperamide or diphenoxylate. If patients remain symptomatic, serotonin receptor antagonists, antihistamines, and somatostatin analogues are the drugs of choice. 5-HT3 receptor antagonists (ondansetron, tropisetron, dolasetron, granisetron, palonosetron, ramosetron, alosetron, and cilansetron) can control diarrhea and nausea and occasionally ameliorate the flushing. A combination of histamine H1 and H2 receptor antagonists (diphenhydramine and cimetidine or ranitidine) may control flushing in patients with upper GI or pulmonary carcinoids. Synthetic analogues of somatostatin (octreotide and lanreotide) are the most widely used agents to control the symptoms of patients with carcinoid syndrome.

Glycine

Synthesis. Glycine is the simplest amino acid.

Degradation. Glycine is broken down by glycine dehydrogenase.

Release. Glycine is released by the inhibitory interneurons in the spinal cord that are activated by group Ia muscle afferents (see page 65). It acts by increasing Cl− conductance in the postsynaptic membrane, hyperpolarizing it, and thus preventing action potential generation.

Histamine

Synthesis. Histamine is synthesized from histidine by histidine decarboxylase.

Degradation. Histamine is degraded by MAO.

Release. Histamine acts as a neurotransmitter in the CNS.

Nitric Oxide

Synthesis. Nitric oxide (NO) is not stored in vesicles. It is synthesized as required in the pre-synaptic terminal from arginine by the enzyme NO synthase.

Degradation. NO has a half-life of only a few seconds.

Release. NO acts as an inhibitory neurotransmitter in the CNS, GI tract, and blood vessels.

Table 2.1 provides examples that are predominantly excitatory or inhibitory.

2.2 Synaptic Transmission

Presynaptic Events

An action potential depolarizes the presynaptic terminal cell membrane, causing membrane Ca2+ channels to open and Ca2+ influx into the presynaptic terminal. This Ca2+ influx then stimulates the release of neurotransmitters from storage vesicles into the synaptic cleft (Fig. 2.1).

Fig. 2.1 Synaptic signal transmission.

An action potential (AP) arriving at the presynaptic membrane (1) causes voltage-gated Ca2+ channels to open (2). This increase in intracellular [Ca2+] triggers the release of neurotransmitters from their storage vesicles into the synaptic cleft (3). Neurotransmitter molecules then diffuse across the synaptic cleft (4) and bind with inotropic or metabotropic receptors on the postsynaptic membrane. Inotropic receptors are ligand-gated ion channels. Ligand (in this case, neurotransmitter) binding (5) causes the inflow of ions into the cell, resulting in either depolarization (inflow of cations) or hyperpolarization (inflow of anions). (6) Ligand binding to metabotropic receptors activates G proteins, which transduce a cellular response via second messenger molecules.

Postsynaptic Events

The neurotransmitters released diffuse across the synaptic cleft and bind to ligand-gated channels on the postsynaptic cell membrane, causing a change in conductance of ions.

– Excitatory postsynaptic potentials (EPSPs) are produced when excitatory neurotransmitters open Na+ channels, resulting in depolarization of the postsynaptic membrane. K+ channels also open, but the combined effect still depolarizes.

– Inhibitory postsynaptic potentials (IPSPs) are produced when inhibitory neurotransmitters open Cl− channels, resulting in stabilization or hyperpolarization of the postsynaptic membrane.

An action potential is generated when the summated EPSPs and IPSPs bring the membrane to threshold. The neurotransmitter dissociates from the receptor and is removed from the synapse via enzymatic degradation, reuptake, or diffusion.

Summation of Postsynaptic Potentials. Postsynaptic neurons summate postsynaptic potentials spatially and temporally to integrate the total excitatory and inhibitory flow (Fig. 2.2).

– Spatial summation is the addition of synaptic depolarizations originating from various regions of the neuron.

– Temporal summation is the synchronicity of depolarizations, with additional depolarizations occurring before previous ones decay.

2.3 Neuromuscular Transmission

The neuromuscular junction is the synapse between motoneurons and skeletal muscle fibers.

Presynaptic Events

An action potential in the motoneuron depolarizes the membrane, causing membrane Ca2+ channels to open and Ca2+ influx into the presynaptic terminal. This Ca2+ influx then stimulates the release of acetylcholine from their storage vesicles into the synaptic cleft.

Postsynaptic Events

Acetylcholine diffuses across the synaptic cleft and interacts with nicotinic receptors on the postsynaptic membrane (motor end plate). The acetylcholine receptor is a Na+ and K+ ion channel. The binding of acetylcholine to this receptor causes an increased conductance of Na+ and K+ at the end plate, creating an end plate potential (EPP).

Botulinum toxin

Botulinum toxin is a neurotoxin produced by the anaerobic bacteria Clostridium botulinum. It prevents the release of acetylcholine at the neuromuscular junction, thereby causing paralysis of skeletal muscles. It is highly potent, and if respiratory muscles are paralyzed, it is lethal. In its purified form (Botox), this paralysis of muscles is temporary (3–4 months) and is used cosmetically to soften the appearance of wrinkles. It is also used therapeutically in the treatment of many conditions, including cervical dystonia (a neuromuscular disorder of the head and neck), severe hyperhydriasis (excessive sweating), achalasia (failure of the lower esophageal sphincter [LES] to relax), and migraine.

Myasthenia gravis

Myasthenia gravis is an autoimmune disease in which there are too few functioning acetylcholine receptors at the neuromuscular junction. P atients with this condition often present in young adulthood with easy fatiguability of muscles, which may progress to permanent muscle weakness. Treatment involves using neostigmine or similar agents to prolong the action of released acetylcholine.

Fig. 2.2 Summation of postsynaptic potentials: (A) spatial summation of stimuli; (B) temporal summation of stimuli.

Multiple presynaptic APs causing excitatory postsynaptic potentials (EPSPs) are summed to stimulate an action potential in the axon hillock of the postsynaptic neuron. The EPSPs may be summated spatially or temporally. In spatial summation (A), multiple APs arrive at the axon hillock simultaneously, and although none of them could generate an AP individually, their summated effect results in an AP. In temporal summation (B), presynaptic APs occurring close together in time generate a large summed EPSP.

End Plate Potentials. End plate potentials (EPPs) result from synchronous release of hundreds of vesicles of acetylcholine from the presynaptic terminal of the motoneuron, causing depolarization of the postsynaptic membrane (Fig. 2.3). This depolarization results in the influx of Na+ through the postsynaptic membrane of the end plate. An action potential is generated when the summated EPPs bring the membrane region surrounding the end plate to threshold, causing the muscle to generate its own action potential. Miniature end plate potentials (MEPPs) occur upon spontaneous release of a single vesicle filled with ~10,000 molecules of neurotransmitter. They depolarize the postsynaptic membrane only 1 mV.

Fig. 2.3 Motor end plate.

Motor end plates are the contact between motor axon terminals and skeletal muscles fibers. The acetylcholine (ACh) vesicles release their contents into the synaptic cleft, where ACh binds with receptors on the sarcolemma. At the neuromuscular junction, motoneurons interface with muscle fibers. APs that travel along motoneurons will stimulate the muscle fibers to contract if the depolarization caused by the release of ACh from the presynaptic terminal reaches threshold and generates an AP at the end plate.

3 Muscle Cell Physiology

3.1 Skeletal Muscle

Structure

Skeletal muscle is composed of long, cylindrical, multinucleated cells called muscle fibers. Each fiber contains a bundle of myofibrils. Myofibrils contain myofilaments, overlapping thick and thin filaments. The filament arrays are arranged into sarcomeres, the functional unit of skeletal muscle cells. Sarcomere units, delimited by Z lines, are linked linearly.

Because the sarcomeres within the myofibrils are in register, the fibers of skeletal muscle have a striated appearance (Fig. 3.1).

Fig. 3.1 Ultrastructure of striated muscle fibers.

Skeletal muscle is composed of bundles of muscle fibers. Each muscle fiber is composed of myofibrils.

Sarcomere Components

Thin Filaments. Thin filaments are made of actin, with the regulatory proteins tropomyosin and troponin positioned along the surface.

Thick Filaments. Thick filaments are made of myosin molecules assembled together with globular heads exposed.

– Titin is a giant protein that keeps the myosin filaments accurately lined up within the sarcomere.

– Cross-bridges are myosin heads that bind to actin filaments.

Sarcomere Organization

Z disks are at either end of a given sarcomere and anchor the thin filaments. The I band is the region near the Z line where there are thin filaments only, without overlap of thick filaments. The A band is the middle part of the sarcomere containing thick filaments. Thin filaments overlap into the A band. The H zone is the area in the center of the A band where the thin filaments do not reach, and there are thick filaments only. The M line is in the center of the H zone (Figs. 3.2, 3.3).

Sarcotubular System

Sarcoplasmic Reticulum. The sarcoplasmic reticulum (SR) is a modified endoplasmic reticulum found only in muscle cells. It consists of a flattened, irregular, saclike system that drapes around the myofibrils. Its membrane contains an active transport Ca2+ pump that is responsible for removing Ca2+ from the cytoplasm and its accumulation within the SR.

Fig. 3.2 Sarcomere structure.

Sarcomeres are bounded by Z disks. The I band contains only thin actin filaments. The A band contains thick filaments and is where the actin and myosin filaments overlap. The H zone solely contains myosin filaments, which thicken toward the middle of the sarcomere to form the M line. Actin is a globular protein molecule. Four hundred such molecules join to form F actin, a beaded polymer chain. Two of the twisted protein filaments combine to form an actin filament. Tropomyosin molecules joined end to end lie adjacent to the actin filaments, and a troponin molecule is attached every 40 nm or so. The sarcomere also has another system of filaments formed by the filamentous protein titin. Titin is anchored to the M and Z plates. Each myosin filament consists of bundles of myosin molecules (see Fig. 3.3).

Fig. 3.3 Myosin II molecule.

Each myosin molecule has two globular heads connected by flexible necks. Each of the heads has a motor domain with a nucleotide binding pocket (for adenosine triphosphate [ATP], or adenosine diphosphate [ADP],+ inorganic phosphate [Pi]) and an actin-binding site. The light protein chains are located on this heavy molecule; one is regulatory, the other, so-called essential. Conformational changes in the head–neck segment allow the myosin head to “tilt” when interacting with actin.

Transverse Tubules. Transverse tubules are deep invaginations of the sarcolemma (the plasma membrane of the muscle fiber) that penetrate into the muscle fiber and allow the m uscle action potential to be directed from the surface into the interior of the muscle fiber.

The sarcoplasmic reticulum adjacent to the transverse tubules is expanded to form terminal cisternae. A transverse tubule and its two adjacent terminal cisternae are linked into a triad.

Muscular dystrophy

Muscular dystrophy is a term used to describe a group of inherited muscle diseases. Each individual type of muscular dystrophy has its own genetic defect. The most common type of muscular dystrophy is due to a genetic defect that causes a mutation in dystrophin, part of a protein complex that conveys force from the Z disks to connective tissue on the surface of the fiber. Dystrophin mutations result in degeneration of muscle fibers with increasing muscle weakness. As the disease progresses, there are muscular contractures with loss of mobility of joints. There is no cure for this group of diseases, but drugs are sometimes used to provide symptomatic relief or to slow its progression. Drugs that help with contractures include phenytoin, carbamazepine, and dantrolene. Prednisone, cyclosporin, and azathioprine may also be used to protect muscle cells from damage. Physical therapy is the mainstay of treatment for muscular dystrophy to try to preserve mobility. Surgery may be used for the relief of contractures.

Innervation

Skeletal muscle is innervated by the somatic nervous system.

Contraction Cycle

Excitation–Contraction Coupling

A motoneuron action potential, by release of acetylcholine at the neuromuscular junction, triggers a muscle action potential that is conducted along the sarcolemma and passes down the transverse tubules. The electrical impulse affects a voltage-sensing protein in the transverse tubule membrane (dihydropyridine receptor), which is linked to a Ca2+ release channel (ryanodine receptor) in the terminal cisterna membrane. Ca2+ is released through these channels into the cytoplasm to induce muscle contraction.

Action of Regulatory Proteins

Cross-bridge binding to thin filaments is controlled by the regulatory proteins troponin and the rodlike tropomyosin. Troponin is made up of three subunits that play specific roles:—Troponin T keeps tropomyosin in the groove of actin.

– Troponin I inhibits the interaction of between the myosin cross-bridges and the actin thin filaments.

– Troponin C binds to Ca2+shifting the position of tropomyosin to expose the binding sites on actin for the myosin cross-bridges.

Cross-Bridge Cycle (Fig. 3.4)

In the resting (relaxed) state, adenosine monophosphate (ADP) and inorganic phosphate (Pi) are bound to the myosin cross-bridge, which is energized, but the cross-bridge cannot attach to actin as the binding sites are blocked by tropomyosin.

– In step 1, due to arrival of an action potential, cytosolic Ca2+rises and Ca2+binds troponin, which shifts tropomyosin, exposing the binding sites on actin and allowing cross-bridge attachment.

– In step 2, Pi and then ADP are released from the cross-bridge, causing the cross-bridge to tilt (the power stroke) and the actin thin filament to slide along the myosin thick filament.

– In step 3, adenosine triphosphate (ATP) attaches to cross-bridge, which results in detachment of the cross-bridge from the actin thin filament.

– In step 4, the bound ATP is hydrolyzed to ADP and Pi, energizing the cross-bridge, and beginning the cycle again.

The cycle repeats if the cytosolic Ca2+ concentration remains high and Ca2+continues to bind to troponin. It ends if reuptake of Ca2+into the sarcoplasmic reticulum (via Ca2+-ATPase) reduces the cytosolic Ca2+ concentration sufficiently so that Ca2+is no longer bound to troponin, causing tropomyosin to shift and once again block the binding sites on actin.

Sliding Filament Mechanism

The rowing action of the myosin cross-bridges in each cycle cause the thin filaments to slide past the thick filaments toward the center of the sarcomere. Sarcomere shortening is manifested in reduction in the distance between Z lines, as well as reductions in the widths of the I band and the H zone. There is no change in the length of the A band.

Twitches and Tetani

The contraction of a muscle fiber following a single action potential is called a twitch.

Rapidly applied stimuli produce tetani (singular tetanus). Sustained contractions representing summation of individual twitches. The resulting tension (force) produced by the muscle is greater than that for a single twitch. The higher concentration of Ca2+ remaining in the cytoplasm during tetanic stimulation is responsible for the increased muscle tension (Fig. 3.5).

Fig. 3.4 Cross-bridge cycle.

Muscle Tension

Isometric, Isotonic, and Eccentric Contractions

– In isometric contraction, external muscle length is held constant.

– In isotonic contraction, the muscle length shortens.

– In eccentric contraction, the muscle exerts a pulling force but is actually getting longer because the external attachments exert more force than is developed within the muscle (Fig. 3.6).

Fig. 3.5 Tetani.

When individual twitches are elicited by rapidly repeating stimuli, the muscle does not relax between stimuli and continuously contracts. This is referred to as a tetanus. Muscle force is significantly greater in a tetanus than in a twitch because more cross-bridges are activated.

Fig. 3.6 Isometric muscle tension relative to sarcomere length.

The length (L) and force (F), or tension, of a muscle are closely related. Because the active force is determined by the magnitude of all potential actin–myosin interactions, it varies with sarcomere length. Skeletal muscle can develop maximum (isometric) force (F0) at its maximum resting length (LMAX). When the sarcomeres shorten (L < LMAX), part of the thin filaments overlap, allowing only forces smaller than F0 to develop. When L is 70% of LMAX, the thick filaments make contact with the Z disks, and F becomes even smaller. In addition, at nonphysiological extensions (L > LMAX), a muscle can develop only restricted force because the number of potentially available actin–myosin bridges is reduced.

The Length–Tension Relationship

The tension developed during isometric contractions at various muscle lengths demonstrates the mechanical properties of muscle tissue and of the sliding filament mechanism.

Passive tension is the force of the elastic elements of a muscle without involvement of the sliding filament apparatus. This is obtained from measurements made on resting, unstimulated muscle. This force is similar to that observed in other elastic structures, such as rubber bands.

Active tension is the force produced by the interaction between myosin and actin at various lengths. This unique curve demonstrates that there is a muscle length at which the sliding filaments will produce their maximum force output. The explanation for the existence of an optimum length is that this sarcomere length produces the maximum amount of overlap between actin and myosin and the largest number of active cross-bridges.

Total tension is the sum of passive and active tension (Fig. 3.7).

The Force–Velocity Relationship