Physiology at a Glance E-Book

Jeremy P. T. Ward

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: At a Glance
• Sprache: Englisch
• Veröffentlichungsjahr: 2017

Seitenzahl: 418

Beschreibung

Extensively revised and updated, this fourth edition of Physiology at a Glance continues to provide a thorough introduction to human physiology, covering a wealth of topics in a comprehensive yet succinct manner. This concise guide breaks this often complex subject down into its core components, dealing with structures of the body from the cellular level to composite systems. New to this edition are three chapters on cell signalling, thermoregulation, and altitude and aerospace physiology, as well as a glossary of terms to aid medical, dental, health science and biomedical students at all levels of their training. Featuring clear, full-colour illustrations, memorable data tables, and easy-to-read text, Physiology at a Glance is ideal as both a revision guide and as a resource to assist basic understanding of key concepts.

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Physiology at a Glance

Fourth Edition

Jeremy P.T. Ward

PhD Professor of Respiratory Cell Physiology Emeritus Professor of Physiology Faculty of Life Sciences & Medicine King's College London London, UK

Roger W.A. Linden

BDS PhD MFDS RCS Emeritus Professor of Craniofacial Biology Faculty of Life Sciences & Medicine King's College London London, UK

This edition first published 2017 © 2017 by John Wiley & Sons, Ltd

Edition History

John Wiley & Sons, Ltd (3e 2013)

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CONTENTS

Preface

Acknowledgements

Abbreviations

About the companion website

Part 1: Introduction

1: Homeostasis and the physiology of proteins

Negative feedback control

Protein form and function are protected by homeostatic mechanisms

2: Body water compartments and physiological fluids

Osmosis

Body water compartments

Intracellular versus extracellular fluid

Interstitial fluid versus plasma

3: Cells, membranes and organelles

Protein-processing organelles

Membranes and membrane proteins

Mitochondria and energy production

4: Membrane transport and ion channels

Carrier-mediated transport

Ion channels

5: Biological electricity

The resting membrane potential

The action potential

6: Conduction of action potentials

Saltatory conduction

Fibre diameters and conduction velocities

Classification of nerve fibres

Compound action potentials

7: Cell signalling

Receptor types

Protein kinases

8: The autonomic nervous system

Sympathetic system

Parasympathetic system

Neurochemical transmission

9: Blood

Plasma proteins

Red blood cells

White blood cells

10: Platelets and haemostasis

Primary haemostasis

Formation of the blood clot (coagulation)

Inhibitors of haemostasis and fibrinolysis

11: Defence: inflammation and immunity

Innate immune response

Antibodies (immunoglobulins)

Adaptive immune response

12: Principles of diffusion and flow

Diffusion and bulk flow

Flow through a tube

Wall tension and pressure in spherical or cylindrical containers

13: Thermoregulation

Thermoregulatory mechanisms

Acclimatization

14: Altitude and aerospace physiology

Altitude

Aerospace

Part 2: Muscles

15: Skeletal muscle and its contraction

Skeletal muscle

General mechanisms of skeletal muscle contraction

Fine structure of skeletal muscle (Figure 15.1)

16: Neuromuscular junction and whole muscle contraction

Neuromuscular junction

Whole muscle contraction

17: Motor units, recruitment and summation

18: Cardiac and smooth muscle

Cardiac muscle

Smooth muscle

Contractile mechanisms of smooth muscle

Part 3: The cardiovascular system

19: Introduction to the cardiovascular system

Blood vessels

The heart

The systemic circulation

The pulmonary circulation

20: The heart

Cardiac valves

Cardiac pacemaker, conduction of the impulse and electrocardiogram

Coronary circulation

21: The cardiac cycle

Ventricular pressure–volume loop

The pulse

Heart sounds

22: Initiation of the heart beat and excitation–contraction coupling

Cardiac muscle electrophysiology

The sinoatrial node and origin of the heart beat

Excitation–contraction coupling (Figure 22.6)

Regulation of contractility: inotropic agents (Figure 22.6)

23: Control of cardiac output and Starling’s law of the heart

Filling pressure and Starling’s law

Importance of Starling’s law

Autonomic nervous system

Venous return and vascular function curves

24: Blood vessels

Structure

Regulation of function and excitation–contraction coupling

The endothelium (Figure 24.5)

25: Control of blood pressure and blood volume

Acute regulation of the mean arterial blood pressure: the baroreceptor reflex

Long-term regulation: control of blood volume (Figure 25.3)

Cardiovascular shock and haemorrhage

26: The microcirculation, filtration and lymphatics

Transcapillary exchange

Filtration (Figure 26.2)

Lymphatics

Oedema

27: Local control of blood flow and specific circulations

Local control of blood flow

Specific circulations

Part 4: The respiratory system

28: Introduction to the respiratory system

Airways (Figure 28.1)

Epithelium and airway clearance

Respiratory muscles

Lung volumes and pressures (Figure 28.5)

29: Lung mechanics

Lung compliance

Surfactant and the alveolar air–fluid interface

Airway resistance

Lung function tests

30: Transport of gases and the gas laws

Partial pressures and fractional concentrations (Figure 30.1)

Gases dissolved in body fluids

Diffusion across the alveolar–capillary membrane (Figure 30.3)

Diffusion and perfusion limitation (Figure 30.3)

31: Carriage of oxygen and carbon dioxide by the blood

Oxygen

Carbon dioxide

Hyperventilation and hypoventilation

32: Control of breathing

The brain stem and central pattern generator

Chemoreception

Lung receptors

33: Ventilation–perfusion matching and right to left shunts

Ventilation–perfusion matching (Figure 33.1)

Effect of gravity

Right to left shunts

Part 5: The renal system

34: Introduction to the renal system

Gross structure

The nephron

Renal circulation

Hormones and the kidney

Micturition

35: Renal filtration

Glomerular filtration

Factors determining the glomerular filtration rate

Measurement of the glomerular filtration rate and the concept of clearance

36: Reabsorption, secretion and the proximal tubule

Tubular transport processes

Tubular transport maximum

The proximal tubule (Figure 36.1)

37: The loop of Henle and distal nephron

The loop of Henle

The distal tubule and collecting duct

38: Regulation of plasma osmolality and fluid volume

Control of plasma osmolality (Figure 38.1)

Control of body fluid volume (Figure 38.4)

Renin, angiotensin and aldosterone

Diuretics

39: Control of acid–base status

Buffers

Proximal renal tubule

Distal renal tubule

Acid–base regulation and compensation

K

+

homeostasis and acid–base status

Part 6: The gut and metabolism

40: Gastrointestinal tract: overview and the mouth

Structure

Saliva and mastication

Swallowing

41: Oesophagus and stomach

Control of gastric secretions

42: Small intestine

Absorption of nutrients

Fats and lipids

43: The exocrine pancreas, liver and gallbladder

The pancreas

The liver

Bile and the gallbladder

44: Large intestine

Defecation

Gut microflora

Part 7: Endocrinology and reproduction

45: Endocrine control

Features of hormonal signalling

Control of hormones

46: Control of metabolic fuels

Control of appetite and body weight

Insulin and glucagon

Diabetes mellitus

47: The hypothalamus and pituitary gland

The anterior pituitary and intermediate lobe

The posterior pituitary

Pulsatile release of pituitary hormones

48: Thyroid hormones and metabolic rate

Synthesis and release

Physiological roles of thyroid hormones

Disorders of the thyroid gland

49: Growth factors

Growth factor families and their receptors

Growth factors and cancer

50: Somatic and skeletal growth

Growth hormone

Bone growth and remodelling

Osteoporosis

51: Control of plasma calcium

Parathyroid hormone and calcitonin

Vitamin D and 1,25-dihydroxycholecalciferol

Other hormones affecting calcium

52: The adrenal glands and stress

The adrenal medulla

The adrenal cortex

53: Endocrine control of reproduction

Actions of gonadotrophins

Hormonal contraceptives

54: Sexual differentiation and function

Sexual differentiation

Puberty

Sexual function

55: Fertilization, pregnancy and parturition

Fertilization

Pregnancy

Parturition

56: Lactation

Hormonal control

Milk let down reflex

Part 8: The sensory and motor systems

57: Introduction to sensory systems

Sensation and perception

Sensory pathways

58: Sensory receptors

59: Special senses: taste and smell

Gustation

Olfaction

60: Special senses: vision

61: Special senses: hearing and balance

Hearing

Balance

62: Motor control and the cerebellum

Motor control

The cerebellum

63: Proprioception and reflexes

Glossary

Appendix I: Comparison of the properties of skeletal, cardiac and smooth muscle

Appendix II: Normal physiological values

Index

EULA

List of Tables

Chapter 17

Table 17.1

Chapter 54

Table 54.1

Guide

Cover

Table of Contents

Preface

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Preface

Physiology is defined as ‘the scientific study of the bodily function of living organisms and their parts'. There is a natural symbiosis between function (physiology) and structure (anatomy) from which physiology emerged as a separate discipline in the late 19th century. A good understanding of anatomy and physiology is an essential prerequisite for understanding what happens when things go wrong – the structural abnormalities and pathophysiology of disease – and as such underpins all biomedical studies and medicine itself. Following a century of reductionism, where the focus of research has progressively narrowed down to the function of individual proteins and genes, there is now a resurgence in integrative physiology, as it has been realized that to make sense of developments such as the Human Genome Project we have to understand body function as an integrated whole. This is considerably more complex than just the sum of its parts because of the multiplicity of interactions involved. True understanding of the role of a single gene, for example, can only be gained when placed in the context of the whole animal, as reflected by the often unexpected effects of knock-out of single genes on the phenotype of mice.

This volume is designed as a concise guide and revision aid to core topics in physiology, and should be useful to all students following a first-year physiology course, whether they are studying single honours, biomedical sciences, nursing, medicine or dentistry. It should also be useful to those studying system-based curricula. The layout of Physiology at a Glance follows that of the other volumes in the At a Glance series, with a two-page spread for each topic (loosely corresponding to a lecture), comprising a large diagram on one page and concise explanatory text on the other. For this fourth edition we have extensively revised the text and figures, there are three completely new chapters, on Cell signalling, Thermoregulation, and Altitude and aerospace physiology, and we have added a Glossary.

Physiology is a large subject, and in a book this size we cannot hope to cover anything but the core and basics. Physiology at a Glance should therefore be used primarily to assist basic understanding of key concepts and as an assistance to revision. Deeper knowledge should be gained by reference to full physiology and system textbooks, and in third-year honours programmes to original peer-reviewed papers. Students may find one or two sections of this book difficult, such as that on the physics of flow and diffusion, and detailed elements of cell signalling. Though such material may not be included in some introductory physiology courses, an understanding of these concepts can assist in learning how body systems behave in the way they do, and in understanding primary research papers.

In revising this fourth edition we have been helped immensely by constructive criticism and suggestions from our colleagues and students, and junior and senior reviewers of the last edition. We thank all those who have given us such advice; any errors are ours and not theirs. We would also like to thank the team at Wiley-Blackwell who provided great encouragement and support throughout the project.

Jeremy Ward Roger Linden

Acknowledgements

Some figures in this book are taken or modified from:

Ward, J.P.T., Ward, J. and Leach, R.M. (2012) The Respiratory System at a Glance (4th edition). Wiley-Blackwell, Oxford.

Aaronson, P.I., Ward, J.P.T. and Connolly, M.J. (2012) The Cardiovascular System at a Glance (4th edition). Wiley-Blackwell, Oxford.

Mehta, A. and Hoffbrand, V. (2009) Haematology at a Glance (3rd edition). Wiley-Blackwell, Oxford.

Abbreviations

1,25-(OH)

2

D

1,25-dihydroxycholecalciferol

2,3-DPG

2,3-diphosphoglycerate

5-HT

5-hydroxytryptamine; serotonin

μG

micro-gravity (weightlessness)

ACE

angiotensin-converting enzyme

ACh

acetylcholine

ACTH

adrenocorticotrophic hormone

ADH

antidiuretic hormone (also called vasopressin)

ADP

adenosine diphosphate

AIDS

acquired immune deficiency syndrome

AMH

anti-Müllerian hormone

AMS

acute mountain sickness

ANP

atrial natriuretic peptide

ANS

autonomic nervous system

AP

action potential

APC

active protein C

or

antigen presenting cell

ATP

adenosine triphosphate

ATPase

enzyme that splits ATP

AV node

atrioventricular node (heart)

AVAs

arteriovenous anastomoses

BAT

brown adipose tissue

BSA

body surface area

BTPS

body temperature and pressure, saturated with water

CaM

calmodulin

CaM-kinase

calcium–calmodulin kinase

cAMP

cyclic adenosine monophosphate

CaSR

calcium-sensing receptor (protein)

CCK

cholecystokinin

CDI

central diabetes insipidus

cGMP

cyclic guanosine monophosphate

CICR

Ca

2+

-induced Ca

2+

release

CNS

central nervous system

CO

cardiac output

COMT

catechol-

O

-methyl transferase

COX

cyclooxygenase

CRH

corticotrophin-releasing hormone

CSF

cerebrospinal fluid

CVP

central venous pressure

Da

Dalton (unit for molecular weight)

DAG

diacylglycerol

DHEA

dehydroepiandrosterone

D

L

o

2

O

2

diffusing capacity in lung; transfer factor

DNA

deoxyribonucleic acid

DOPA

dihydroxyphenylalanine

E

(ion)

equilibrium potential for ion (e.g. K

+

, Na

+

, Ca

2+

or Cl

–

)

ECF

extracellular fluid

ECG (EKG)

electrocardiogram (or graph)

EDP

end diastolic pressure

EDV

end diastolic volume

EGF

epidermal growth factor

E

m

membrane potential

EMG

electromyogram

EPO

erythropoietin

EPP

end plate potential

ERV

expiratory reserve volume

ESV

end systolic volume

ETC

electron transport chain

F

ab

hypervariable region of antibody molecule

F

c

constant region of antibody molecule

FEV

1

forced expiratory volume in 1 s

FFA

free fatty acids

FGF

fibroblast growth factor

F

N

2

(F

O

2

)

fractional concentration of nitrogen (oxygen) in a gas mixture

FRC

functional residual capacity

FSH

follicle-stimulating hormone

FVC

forced vital capacity

G-LOC

G-forces induced loss of consciousness

G-protein

GTP-binding protein

GDP

guanosine diphosphate

GFR

glomerular filtration rate

GH

growth hormone

GHRH

growth hormone-releasing hormone

GI

gastrointestinal

GIP

gastric inhibitory peptide

GLP-1

glucagon-like peptide 1

GLUT-1, 2 or 4

glucose transporters

GnRH

gonadotrophin-releasing hormone

GPCR

G-protein-coupled receptor

GRP

gastrin-releasing peptide

GTP

guanosine triphosphate

GTPase

enzyme that splits GTP

HACE

high-altitude cerebral oedema

HAPE

high-altitude pulmonary oedema

[Hb]

haemoglobin concentration

HbA

adult haemoglobin

HbF

fetal haemoglobin

hCG

human chorionic gonadotrophin

HIV

human immunodeficiency virus

HMWK

high molecular weight kininogen

ICF

intracellular fluid

IgA, E, G, M

immunoglobulin A, E, G or M

IGF-1 or 2

insulin-like growth factor (1 or 2)

IL-1b or 6

interleukin-1β or 6

IP

3

inositol trisphosphate

IRS-1

insulin receptor substrate 1

IRV

inspiratory reserve volume

ISF

interstitial fluid

JAK

Janus kinase

JGA

juxtaglomerular apparatus

LH

luteinizing hormone

MAO

monoamine oxidase

MAP

mean arterial pressure

MAPK(K)

mitogen-activated protein kinase (kinase)

MEPP

miniature end plate potentials

MHC I, II

major histocompatibility complex I or II

MIH

melanotrophin-inhibiting hormone

MLC

myosin light chain

MLCK

myosin light chain kinase

MLCP

myosin light chain phosphatase

mRNA

messenger RNA

MSH

melanotrophin-stimulating hormone

Na

+

pump

Na

+

-K

+

ATPase

NAD

+

or (NADH)

nicotinic adenine dinucleotide (oxidized and reduced forms)

NCX

Na

+

-Ca

2+

exchanger

NDI

nephrogenic diabetes insipidus

NGF

nerve growth factor

NK

natural killer (cells)

NMJ

neuromuscular junction

NO

nitric oxide

NOS

nitric oxide synthase

P2Y or P2X

purinergic receptor type 2Y or 2X

PAH

para

-aminohippuric acid

PAMP

pathogen-associated molecular pattern

P

B

barometric pressure

PDGF

platelet-derived growth factor

PEFR

peak expiratory flow rate

PGE

2

prostaglandin E

2

PGI

2

prostacyclin (prostaglandin I

2

)

PI-3 kinase

phosphatidylinositol-3 kinase

pK

negative log of dissociation constant (buffers)

PKA

protein kinase A

PKC

protein kinase C

PKG

protein kinase G

PLA

2

phospholipase A2

PLC

phospholipase C

PMCA

plasma membrane Ca

2+

ATPase

P

O

2

partial pressure of oxygen

PRR

pattern recognition receptor

PTH

parathyroid hormone

Ras, Rho

small monomeric GTPases

ROC

receptor-operated channels

ROMK

renal outer medullary potassium channel

RPF

renal plasma flow

RTK

receptor tyrosine kinase

RV

residual volume

or

right ventricle

SA node

sinoatrial node

SERCA

smooth endoplasmic reticulum Ca

2+

ATPase

SH2

Src-homology 2

SMAD

intracellular protein associated with streptokinases

SOC

store-operated channels

SP

Substance P

SR

sarcoplasmic reticulum

Src

a non-receptor tyrosine kinase

SST

somatostatin

STAT

signal transduction and activation of transcription (protein)

STIM

stromal interaction molecule

STPD

standard temperature and pressure, dry gas

SV

stroke volume

SWVP

saturated water vapour pressure

T

1 or 2

mono- or di-iodotyrosine

T

3

tri-iodothyronine

T

4

thyroxine

T

C

Core temperature

TF

tissue factor

TGFβ

transforming growth factor β

TH

thyroid hormone

TLC

total lung capacity

T

m

tubular transport maximum (kidney)

TNF

tumour necrosis factor

TNZ

thermoneutral zone

tPA

tissue plasminogen activator

TPR

total peripheral resistance

TRa

thyroid hormone receptor

TRE

thyroid response element

tRNA

transfer RNA

TSH

thyroid-stimulating hormone

TUC

time of useful consciousness

TV

tidal volume

TXA

2

thromboxane A

2

UCP-1, 2 or 3

uncoupling protein-1, 2 or 3

V

A

/Q mismatch

ventilation–perfusion mismatch (lungs)

VC

vital capacity

VIP

vasoactive intestinal polypeptide

vWF

von Willebrand factor

About the companion website

This book is accompanied by a companion website:

www.ataglanceseries.com/physiology

The website features:

Interactive multiple choice questions

Revision notes

Interactive self-test flashcards

Part 1Introduction

Chapters

1: Homeostasis and the physiology of proteins

2: Body water compartments and physiological fluids

3: Cells, membranes and organelles

4: Membrane transport and ion channels

5: Biological electricity

6: Conduction of action potentials

7: Cell signalling

8: The autonomic nervous system

9: Blood

10: Platelets and haemostasis

11: Defence: inflammation and immunity

12: Principles of diffusion and flow

13: Thermoregulation

14: Altitude and aerospace physiology

1Homeostasis and the physiology of proteins

Claude Bernard (1813–1878) first described ‘le mileau intérieur’ and observed that the internal environment of the body remained remarkably constant (or in equilibrium) despite the ever changing external environment. The term homeostasis was not used until 1929 when Walter Cannon first used it to describe this ability of physiological systems to maintain conditions within the body in a relatively constant state of equilibrium. It is arguably the most important concept in physiology.

Homeostasis is Greek for ‘staying the same’. However, this so-called equilibrium is not an unchanging state but is a dynamic state of equilibrium causing a dynamic constancy of the internal environment. This dynamic constancy arises from the variable responses caused by changes in the external environment. Homeostasis maintains most physiological systems and examples are seen throughout this book. The way in which the body maintains the H+ ion concentration of body fluids within narrow limits, the control of blood glucose by the release of insulin, and the control of body temperature, heart rate and blood pressure are all examples of homeostasis. The human body has literally thousands of control systems. The most intricate are genetic control systems that operate in all cells to control intracellular function as well as all extracellular functions. Many others operate within organs to control their function; others operate throughout the body to control interaction between organs. As long as conditions are maintained within the normal physiological range within the internal environment, the cells of the body continue to live and function properly. Each cell benefits from homeostasis and in turn, each cell contributes its share towards the maintenance of homeostasis. This reciprocal interplay provides continuity of life until one or more functional systems lose their ability to contribute their share. Moderate dysfunction of homeostasis leads to sickness and disease, and extreme dysfunction of homeostasis leads to death.

Negative feedback control

Most physiological control mechanisms have a common basic structure. The factor that is being controlled is called the variable. Homeostatic mechanisms provide the tight regulation of all physiological variables and the most common type of regulation is by negative feedback. A negative feedback system (Figure 1.1) comprises: detectors (often neural receptor cells) to measure the variable in question; a comparator (usually a neural assembly in the central nervous system) to receive input from the detectors and compare the size of the signal against the desired level of the variable (the set point); and effectors (muscular and/or glandular tissue) that are activated by the comparator to restore the variable to its set point. The term ‘negative feedback’ comes from the fact that the effectors always act to move the variable in the opposite direction to the change that was originally detected. Thus, when the partial pressure of CO2 in blood increases above 5.3  kPa (40  mmHg), brain stem mechanisms increase the rate of ventilation to clear the excess gas, and vice versa when CO2 levels fall below 5.3  kPa (Chapter 32). The term ‘set point’ implies that there is a single optimum value for each physiological variable; however, there is some tolerance in all physiological systems and the set point is actually a narrow range of values within which physiological processes will work normally (Figure 1.2). Not only is the set point not a point, but it can be reset in some systems according to physiological requirements. For instance, at high altitude, the low partial pressure of O2 in inspired air causes the ventilation rate to increase. Initially, this effect is limited due to the loss of CO2, but, after 2–3 days, the brain stem lowers the set point for CO2 and allows ventilation to increase further, a process known as acclimatization (Chapter 14).

A common operational feature of all negative feedback systems is that they induce oscillations in the variable that they control (Figure 1.2). The reason for this is that it takes time for a system to detect and respond to a change in a variable. This delay means that feedback control always causes the variable to overshoot the set point slightly, activating the opposite restorative mechanism to induce a smaller overshoot in that direction, until the oscillations fall within the range of values that are optimal for physiological function. Normally, such oscillations have little visible effect. However, if unusually long delays are introduced into a system, the oscillations can become extreme. Patients with congestive heart failure sometimes show a condition known as Cheyne–Stokes’ breathing, in which the patient undergoes periods of deep breathing interspersed with periods of no breathing at all (apnoea). This is partly due to the slow flow of blood from the lungs to the brain, which causes a large delay in the detection of blood levels of CO2.

Some physiological responses use positive feedback, causing rapid amplification. Examples include initiation of an action potential, where sodium entry causes depolarization which further increases sodium entry and thus more depolarization (Chapter 5), and certain hormonal changes, particularly in reproduction (Chapter 53). Positive feedback is inherently unstable, and requires some mechanism to break the feedback loop and stop the process (an off switch), such as time-dependent inactivation of sodium channels in the first example and the birth of the child in the second.

Protein form and function are protected by homeostatic mechanisms

The homeostatic mechanisms that are described in detail throughout this book have evolved to protect the integrity of the protein products of gene translation. Normal functioning of proteins is essential for life, and usually requires binding to other molecules, including other proteins. The specificity of this binding is determined by the three-dimensional shape of the protein. The primary structure of a protein is determined by the sequence of amino acids (Figure 1.3). Genetic mutations that alter this sequence can have profound effects on the functionality of the final molecule. Such gene polymorphisms are the basis of many genetically based disorders. The final shape of the molecule (the tertiary structure), however, results from a process of folding of the amino acid chain (Figure 1.4). Folding is a complex process by which a protein achieves its lowest energy conformation. It is determined by electrochemical interactions between amino acid side-chains (e.g. hydrogen bonds, van der Waals’ forces), and is so vital that it is overseen by molecular chaperones, such as the heat shock proteins, which provide a quiet space within which the protein acquires its final shape. In healthy tissue, cells can detect and destroy misfolded proteins, the accumulation of which damages cells and is responsible for various pathological conditions, including Alzheimer's disease and Creutzfeldt–Jakob disease. Folding ensures that the functional sequences of amino acids (domains) that form, e.g. binding sites for other molecules or hydrophobic segments for insertion into a membrane, are properly orientated to allow the protein to serve its function.

The relatively weak nature of the forces that cause folding renders them sensitive to changes in the environment surrounding the protein. Thus, alterations in acidity, osmotic potential, concentrations of specific molecules/ions, temperature or even hydrostatic pressure can modify the tertiary shape of a protein and change its interactions with other molecules. These modifications are usually reversible and are exploited by some proteins to detect alterations in the internal or external environments. For instance, nerve cells that respond to changes in CO2 (chemoreceptors; Chapter 32) possess ion channel proteins (Chapter 4) that open or close to generate electrical signals (Chapter 5) when the acidity of the medium surrounding the receptor (CO2 forms an acid in solution) alters by more than a certain amount. However, there are limits to the degree of fluctuation in the internal environment that can be tolerated by proteins before their shape alters so much that they become non-functional or irreversibly damaged, a process known as denaturation (this is what happens to egg-white proteins in cooking). Homeostatic systems prevent such conditions from arising within the body, and thus preserve protein functionality.

2Body water compartments and physiological fluids

Osmosis

Osmosis is the passive movement of water across a semi-permeable membrane from regions of low solute concentration to those of higher solute concentration. Biological membranes are semi-permeable in that they usually allow the free movement of water but restrict the movement of solutes. The creation of osmotic gradients is the primary method for the movement of water in biological systems. This is why the osmotic potential (osmolality) of body fluids is closely regulated by a number of homeostatic mechanisms (Chapter 38). A fluid at the same osmotic potential as plasma is said to be isotonic; one at higher potential (i.e. more concentrated solutes) is hypertonic and one at lower potential is hypotonic. The osmotic potential depends on the number of osmotically active particles (molecules) per litre, irrespective of their identity. It is expressed in terms of osmoles, where 1 osmole equals 1 mole of particles, as osmolarity (osmol/L), or osmolality (osmol/kg H2O). The latter is preferred by physiologists as it is independent of temperature, though in physiological fluids the values are very similar. The osmolality of plasma is ∼290  mosmol/kg H2O, mostly due to dissolved ions and small molecules (e.g. glucose and urea). These diffuse easily across capillaries, and the crystalloid osmotic pressure they exert is therefore the same either side of the capillary wall. Proteins do not easily pass through capillary walls, and are responsible for the oncotic (or colloidal osmotic) pressure. This is much smaller than crystalloid osmotic pressure, but is critical for fluid transfer across capillary walls because it differs between plasma and interstitial fluid (Chapter 26). Oncotic pressure is expressed in terms of pressure, and in plasma is normally ∼25  mmHg. Maintenance of plasma osmolality is vital for regulation of blood volume (Chapter 25). Drinking fluids of differing osmotic potentials has distinct effects on the distribution of water between cells and extracellular fluid (Figure 2.2).

Body water compartments

Water is the solvent in which almost all biological reactions take place (the other being membrane lipid), and so it is fitting that it accounts for some 50–70% of the body mass (i.e. about 40  L in a 70  kg person). The nature of biological membranes means that water moves freely within the body, but the materials dissolved in it do not. There are two major ‘fluid compartments’: the water within cells (intracellular fluid, ICF), which accounts for about 65% of the body total, and the water outside cells (extracellular fluid, ECF). These compartments are separated by the plasma membranes of the cells, and differ markedly in terms of the concentrations of the ions that are dissolved in them (Figure 2.1; Chapter 4). Approximately 65% of the ECF comprises the tissue fluid found between cells (interstitial fluid, ISF), and the rest is made up of the liquid component of blood (plasma). The barrier between these two fluids consists of the walls of the capillaries (Figure 2.1; Chapter 26).

Intracellular versus extracellular fluid

Many critical biological events, including all bioelectrical signals (Chapter 5), depend on maintaining the composition of physiological fluids within narrow limits. Figure 2.1 shows the concentrations of ions in the three main fluid compartments. It should be noted that, within any one compartment, there must be electrical neutrality, i.e. the total number of positive charges must equal the total number of negative charges. The most important difference between ICF and ECF lies in the relative concentrations of cations. The K+ ion concentration is much higher inside the cell than in ECF, while the opposite is true for the Na+ ion concentration. Ca2+ and Cl− ion concentrations are also higher in ECF. The question arises as to how these differences come about, and how they are maintained. Ion channel proteins allow the cell to determine the flow of ions across its own membrane (Chapter 4). In most circumstances, relatively few channels are open so that the leakage of ions is low. There is, however, always a steady movement of ions across the membrane, with Na+ and K+ following their concentration gradients into and out of the cell, respectively. Uncorrected, the leak would eventually lead to the equalization of the compositions of the two compartments, effectively eliminating all bioelectrical signalling (Chapter 5). This is prevented by the activity of the Na+-K+ ATPase, or Na+ pump (Chapter 3). Of the other ions, most Ca2+ in the cell is transported actively either out of the cell or into the endoplasmic reticulum and mitochondria, leaving very low levels of free Ca2+ in ICF. Cl− ions are differentially distributed across the membrane by virtue of their negative charge. Intracellular proteins are negatively charged at physiological pH. These and other large anions that cannot cross the plasma membrane (e.g. phosphate, PO43−) are trapped within the cell and account for most of the anion content of ICF. Cl− ions, which can diffuse across the membrane through channels, are forced out of the cell by the charge on the fixed anions. The electrical force driving Cl− ions out of the cell is balanced by the chemical gradient driving them back in, a situation known as the Gibbs–Donnan equilibrium. Variations in the large anion content of cells mean that the concentration of Cl− ions in ICF can vary by a factor of 10 between cell types, being as high as 30  mM in cardiac myocytes, although lower values (around 5  mM) are more common.

Interstitial fluid versus plasma

The main difference between these fluids is that plasma contains more protein than does ISF (Figure 2.1). The plasma proteins (Chapter 9) are the only constituents of plasma that do not cross into ISF, although they are allowed to escape from capillaries in very specific circumstances (Chapter 11). The presence of impermeant proteins in the plasma exerts an osmotic force relative to ISF (plasma oncotic pressure; see previously) that almost balances the hydrostatic pressure imposed on the plasma by the action of the heart, which tends to force water out of the capillaries, so that there is a small net water movement out of the plasma into the interstitial space. The leakage is absorbed by the lymphatic system (Chapter 26). Transcellular fluid is the name given to fluids that do not contribute to any of the main compartments, but which are derived from them. It includes cerebrospinal fluid and exocrine secretions, particularly gastrointestinal secretions (Chapters 40–44), and has a collective volume of approximately 2  L.

3Cells, membranes and organelles

The aqueous internal environment of the cell is separated from the aqueous external medium by an envelope of fat molecules (lipids) known as the plasma membrane. About half the cell is filled with cytosol, a viscous, protein-rich fluid between the internal structures. These consist of organelles which are themselves enclosed by lipid membranes, and components of the cytoskeleton such as microtubules and actin filaments which provide structural stability and the ability of the cell to change shape or move. The reticular appearance of the cell interior is due to organelles whose membranes are folded to maximize surface area. These include the rough endoplasmic reticulum and Golgi apparatus, which are involved in protein assembly, and the smooth endoplasmic reticulum which serves as a store for intracellular Ca2+ and is the major site of lipid production (Figure 3.1). The arrangement of structures within the cell is highly organized, but also dynamic; organelles and structures can be rearranged according to need and function (e.g. cell division or migration).

Protein-processing organelles

The nucleus (Figure 3.1) contains the chromosomes and nucleolus, a membrane-less structure responsible for production of ribosomes. Ribosomes translocate to the rough endoplasmic reticulum (giving it its appearance), where they are responsible for protein assembly. The endoplasmic reticulum and Golgi apparatus perform post-translational processing of new proteins. This includes trimming amino acid chains to the right length, protein folding, addition of polysaccharide chains (glycosylation) and identification of improperly folded proteins. These and other proteins for recycling are tagged with multiple ubiquitin molecules, allowing them to be recognized and destroyed by proteasomes (proteolytic protein complexes). Proteins are delivered from the Golgi apparatus to specific intracellular destinations. For example, receptor and structural proteins are sent to the membrane and digestive enzymes to lysosomes, and molecules for extracellular action are packaged into secretory vesicles. Lysosomes are small vesicles containing acid hydrolase enzymes which catabolize macromolecules. They work optimally at pH 5.0, and as cytosolic pH is ∼7.2, any leaking into the cytosol cannot attack the cell inappropriately. Lysosomes digest endocytosed, unwanted and defective proteins, thereby recycling raw materials and preventing accumulation of rubbish.

Membranes and membrane proteins

Membrane lipids (mostly phospholipids) comprise a hydrophilic (water-loving) head, with two short hydrophobic (water-repelling) fatty acid tails (Figure 3.2). In an aqueous medium they self-organize into a bilayer with the heads facing outwards and the tails inwards (Figure 3.2). They diffuse freely within each layer (lateral diffusion) so the membrane is fluid. The hydrophobic interior and hydrophilic exterior of the membrane means that lipid-soluble (hydrophobic) substances such as cholesterol incorporate into the membrane, whilst molecules with both hydrophobic and hydrophilic domains such as proteins can be tethered part in and part out of the membrane (the fluid mosaic model; Figure 3.2). Many such molecules provide signalling, transport or structural functions. The latter are provided by proteins such as spectrin, which binds to the inner layer and forms an attachment framework for the cytoskeleton. Lipid-soluble molecules such as O2 and CO2, and small molecules such as water and urea readily pass through the lipid bilayer. However, larger molecules such as glucose and polar (charged) molecules such as ions cannot, and their transport is mediated by transporter and ion channel membrane proteins (Chapter 4). Proteins and large particles can also be engulfed by membrane segments to form intracellular vesicles (endocytosis). Membrane components can diffuse laterally and move around the membrane. However, the cell can control exactly which proteins insert into which portion of the membrane. For example, cells lining the kidney tubules are polarized so that Na+–K+ ATPase transporters (Chapters 4 and 36) are located only on one side of the cell. Most cells are covered by a thin gel-like layer called the glycocalyx, containing glycoproteins and carbohydrate chains extending from the membrane and secreted proteins (Figure 3.2). It protects the membrane and also plays a role in cell function and cell–cell interactions.

Numerous membrane proteins are associated with cell signalling (see Chapter 7). These include enzymes bound to the inner surface (e.g. phospholipase), and transmembrane proteins such as receptors, transporters and ion channels (Figure 3.2) which penetrate the entire thickness of the bilayer. The intramembrane segments of such proteins are composed of hydrophobic amino acid residues whilst the extra- and intra-cellular portions predominantly contain hydrophilic residues. Other transmembrane proteins such as integrins and cadherins provide structural and signalling links with other cells and the extracellular matrix (Figure 3.2). Their cytosolic ends bind to components of the cytoskeleton, including protein kinases which can initiate or modulate processes such as gene transcription, cell growth or changes in cell shape.

Mitochondria and energy production

Mitochondria use molecular oxygen to, in effect, burn sugar and small fatty acid molecules to produce adenosine triphosphate (ATP), which is used by all energy-requiring cellular reactions. Glucose is first converted to pyruvate in the cytosol by glycolysis, producing in the process a small net amount of ATP and reduced nicotinic adenine dinucleotide (NADH). Glycolysis does not require O2, so when O2 is limited, this anaerobic respiration can supply some ATP, with NADH being reoxidized to NAD+ by metabolism of the pyruvate to lactate (Figure 3.3). However, under normal conditions where there is sufficient O2, oxidative phosphorylation in the mitochondria produces ∼15-fold more ATP for each glucose molecule than does glycolysis. Pyruvate and fatty acids transported into the mitochondrial matrix act as substrates for enzymes that drive the citric acid (Krebs’) cycle, which generates NADH and the waste product CO2. The electron transport chain, a series of enzymes in the inner mitochondrial membrane, then uses molecular O2 to re-oxidize NADH to NAD+. In doing so, it generates a H+ ion gradient across the inner membrane which drives the ATP synthase (Figure 3.3). Note that mitochondria are not solely devoted to ATP production, as they are also involved in other cellular processes, including Ca2+ homeostasis and signalling. The mitochondria are also the major source of body heat production (see Chapter 13).

5Biological electricity

Electrical events in biological tissues are caused by the movement of ions across the membrane. A potential difference exists across the membranes of all cells (membrane potential, Em), but only excitable tissues can generate action potentials