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Cellular Physiology of Nerve and Muscle E-Book

Gary G. Matthews

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Herausgeber: John Wiley & Sons
Kategorie: Wissenschaft und neue Technologien
Sprache: Englisch

Beschreibung

Cellular Physiology of Nerve and Muscle, Fourth Edition offers a state of the art introduction to the basic physical, electrical and chemical principles central to the function of nerve and muscle cells.

The text begins with an overview of the origin of electrical membrane potential, then clearly illustrates the cellular physiology of nerve cells and muscle cells. Throughout, this new edition simplifies difficult concepts with accessible models and straightforward descriptions of experimental results.

An all-new introduction to electrical signaling in the nervous system.
Expanded coverage of synaptic transmission and synaptic plasticity.
A quantitative overview of the electrical properties of cells.
New detailed illustrations.

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Seitenzahl: 370

Veröffentlichungsjahr: 2013

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Leseprobe

Contents

Preface

Acknowledgments

Part I: Origin of Electrical Membrane Potential

1 Introduction to Electrical Signaling in the Nervous System

The Patellar Reflex as a Model for Neural Function

The Cellular Organization of Neurons

Electrical Signals in Neurons

Transmission between Neurons

2 Composition of Intracellular and Extracellular Fluids

Intracellular and Extracellular Fluids

The Structure of the Plasma Membrane

Summary

3 Maintenance of Cell Volume

Molarity, Molality, and Diffusion of Water

Osmotic Balance and Cell Volume

Summary

4 Membrane Potential: Ionic Equilibrium

Diffusion Potential

Equilibrium Potential

Incorporating Osmotic Balance

Donnan Equilibrium

A Model Cell that Looks Like a Real Animal Cell

The Sodium Pump

Summary

5 Membrane Potential: Ionic Steady State

Equilibrium Potentials for Sodium, Potassium, and Chloride

Ion Channels in the Plasma Membrane

Membrane Potential and Ionic Permeability

The Goldman Equation

Ionic Steady State

The Chloride Pump

Electrical Current and the Movement of Ions Across Membranes

Factors Affecting Ion Current Across a Cell Membrane

Membrane Permeability vs. Membrane Conductance

Behavior of Single Ion Channels

Summary

Part II: Cellular Physiology of Nerve Cells

6 Generation of Nerve Action Potential

The Action Potential

Initiation and Propagation of Action Potentials

Changes in Relative Sodium Permeability During an Action Potential

Propagation of an Action Potential Along a Nerve Fiber

Factors Affecting the Speed of Action Potential Propagation

Molecular Properties of the Voltage-sensitive Sodium Channel

Molecular Properties of Voltage-dependent Potassium Channels

Calcium-dependent Action Potentials

Summary

7 The Action Potential: Voltage-clamp Experiments

The Voltage Clamp

The Gated Ion Channel Model

Summary

8 Synaptic Transmission at the Neuromuscular Junction

Chemical and Electrical Synapses

The Neuromuscular Junction as a Model Chemical Synapse

Neurotransmitter Release

Summary

9 Synaptic Transmission in the Central Nervous System

Excitatory and Inhibitory Synapses

Excitatory Synaptic Transmission Between Neurons

Inhibitory Synaptic Transmission

The Family of Neurotransmitter-gated Ion Channels

Neuronal Integration

Indirect Actions of Neurotransmitters

Presynaptic Inhibition and Facilitation

Synaptic Plasticity

Summary

Part III: Cellular Physiology of Muscle Cells

10 Excitation–Contraction Coupling in Skeletal Muscle

The Three Types of Muscle

Structure of Skeletal Muscle

Regulation of Contraction

Summary

11 Neural Control of Muscle Contraction

The Motor Unit

The Mechanics of Contraction

Control of Muscle Tension by the Nervous System

Summary

12 Cardiac Muscle: The Autonomic Nervous System

Autonomic Control of the Heart

Summary

Appendix A: Derivation of the Nernst Equation

Appendix B: Derivation of the Goldman Equation

Appendix C: Electrical Properties of Cells

Part I

Origin of Electrical Membrane Potential

This book is about the physiological characteristics of nerve and muscle cells. As we shall see, the ability of these cells to generate and conduct electricity is fundamental to their functioning. Thus, to understand the physiology of nerve and muscle, we must understand the basic physical and chemical principles underlying the electrical behavior of cells.

Because an understanding of how electrical voltages and currents arise in cells is central to our goals in this book, Part I is devoted to this task. The discussion begins with the differences in composition of the fluids inside and outside cells and culminates in a quantitative understanding of how ionic gradients across the cell membrane give rise to a transmembrane voltage. This quantitative description sets the stage for the specific descriptions of nerve and muscle cells in Parts II and III of the book and is central to understanding how the nervous system functions as a transmitter of electrical signals.

1 Introduction to Electrical Signaling in the Nervous System

The Patellar Reflex as a Model for Neural Function

To set the stage for discussing the generation and transmission of signals in the nervous system, it will be useful to describe the characteristics of those signals using a simple example: the patellar reflex, also known as the knee-jerk reflex. Figure 1-1 shows the neural circuitry underlying the patellar reflex. Tapping the patellar tendon, which connects the knee cap (patella) to the bones of the lower leg, pulls the knee cap down and stretches the quadriceps muscle at the front of the thigh. Specialized nerve cells (sensory neurons) sense the stretch of the muscle and send a signal that travels along the thin fibers of the sensory neurons from the muscle to the spinal cord. In the spinal cord, the sensory signal is received by other neurons, called motor neurons. The motor neurons send nerve fibers back to the quadriceps muscle and command the muscle to contract, which causes the knee joint to extend.

Figure 1-1 A schematic representation of the patellar reflex. The sensory neuron is activated by stretching the thigh muscle. The incoming (afferent) signal is carried to the spinal cord along the nerve fiber of the sensory neuron. In the spinal cord, the sensory neuron activates motor neurons, which in turn send outgoing (efferent) signals along the nerve back to the thigh muscle, causing it to contract.

The reflex loop exemplified by the patellar reflex embodies in a particularly simple way all of the general features that characterize the operation of the nervous system. A sensory stimulus (muscle stretch) is detected, the signal is transmitted rapidly over long distance (to and from the spinal cord), and the information is focally and specifically directed to appropriate targets (the quadriceps motor neurons, in the case of the sensory neurons, and the quadriceps muscle cells, in the case of the motor neurons). The sensory pathway, which carries information into the nervous system, is called the afferentpathway, and the motor output constitutes the efferent pathway. Much of the nervous system is devoted to processing afferent sensory information and then making the proper connections with efferent pathways to ensure that an appropriate response occurs. In the case of the patellar reflex, the reflex loop ensures that passive stretch of the muscle will be automatically opposed by an active contraction, so that muscle length remains constant.

The Cellular Organization of Neurons

Neurons are structurally complex cells, with long fibrous extensions that are specialized to receive and transmit information. This complexity can be appreciated by examining the structure of a motor neuron, shown schematically in Figure 1-2a. The cell body, or soma, of the motor neuron—where the nucleus resides—is only about 20–30 µm in diameter in the case of motor neurons involved in the patellar reflex. The soma is only a small part of the neuron, however, and it gives rise to a tangle of profusely branching processes called dendrites, which can spread out for several millimeters within the spinal cord. The dendrites are specialized to receive signals passed along as the result of the activity of other neurons, such as the sensory neurons of the patellar reflex, and to funnel those signals to the soma. The soma also gives rise to a thin fiber, the axon, that is specialized to transmit signals over long distances. In the case of the motor neuron in the patellar reflex, the axon extends all the way from the spinal cord to the quadriceps muscle, a distance of approximately 1 meter. As shown in Figure 1-2b, the sensory neuron of the patellar reflex is structurally simpler than the motor neuron. Its soma, which is located just outside the spinal cord in the dorsal root ganglion, gives rise to only a single nerve fiber, the axon. The axon splits into two branches shortly after it exits the dorsal root ganglion: one branch extends away from the spinal cord to contact the muscle cells of the quadriceps muscle, and the other branch passes into the spinal cord to contact the quadriceps motor neurons. The axon of the sensory neuron carries the signal generated by muscle stretch from the muscle into the spinal cord. Because the sensory neuron receives its input signal from the sensory stimulus (muscle stretch) at the peripheral end of the axon instead of from other neurons, it lacks the den-drites seen in the motor neuron.

Figure 1-2 Structures of single neurons involved in the patellar reflex.

Electrical Signals in Neurons

To transmit information rapidly over long distances, neurons produce active electrical signals, which travel along the axons that make up the transmission paths. The electrical signal arises from changes in the electrical voltage difference across the cell membrane, which is called the membrane potential.Although this transmembrane voltage is small—typically less than a tenth of a volt—it is central to the functioning of the nervous system. Information is transmitted and processed by neurons by means of changes in the membrane potential.

What does the electrical signal that carries the message along the sensory nerve fiber in the patellar reflex look like? To answer this question, we must measure the membrane potential of the sensory neuron by placing an ultrafine voltage-sensing probe, called an intracellular microelectrode, inside the sensory nerve fiber, as illustrated in Figure 1-3. A voltmeter is connected to measure the voltage difference between the tip of the intracellular microelectrode (point a in the figure) and a reference point in the extracellular space (point b). When the microelectrode is located outside the sensory neuron, both points a and b are in the extracellular space, and the voltmeter therefore records no voltage difference (Figure 1-3b). When the tip of the probe is inserted inside the sensory neuron, however, the voltmeter measures an electrical potential between points a and b, representing the voltage difference between the inside and the outside of the neuron—that is, the membrane potential of the neuron. As shown in Figure 1-3b, the inside of the sensory nerve fiber is negative with respect to the outside by about seventy-thousandths of a volt (1 millivolt, abbreviated mV, equals one-thousandth of a volt). Because the potential outside the cell is our reference point and the inside is negative with respect to the outside, the membrane potential is represented as a negative number, i.e., –70 mV.

As long as the sensory neuron is not stimulated by stretching the muscle, the membrane potential remains constant at this resting value. For this reason, the unstimulated membrane potential is known as the resting potential of the cell. When the muscle is stretched, however, the membrane potential of the sensory neuron undergoes a dramatic change, as shown in Figure 1-3b. After a delay that depends on the distance of the recording site from the muscle, the membrane potential suddenly moves in the positive direction, transiently reverses sign for a brief period, and then returns to the resting negative level. This transient jump in membrane potential is the action potential—the long-distance signal that carries information in the nervous system.

Transmission between Neurons

What happens when the action potential reaches the end of the neuron, and the signal must be transmitted to the next cell? In the patellar reflex, signals are relayed from one cell to another at two locations: from the sensory neuron to the motor neuron in the spinal cord, and from the motor neuron to the muscle cells in the quadriceps muscle. The point of contact where signals are transmitted from one neuron to another is called a synapse. In the patellar reflex, both the synapse between the sensory neuron and the motor neuron and the synapse between the motor neuron and the muscle cells are chemical synapses, in which an action potential in the input cell (the presynaptic cell) causes it to release a chemical substance, called a neurotransmitter. The molecules of neuro-transmitter then diffuse through the extracellular space and change the membrane potential of the target cell (the postsynaptic cell). The change in membrane potential of the target then affects the firing of action potentials Neurotransmitter changes electrica potential of postsynaptic cell by the postsynaptic cell. This sequence of events during synaptic transmission is summarized in Figure 1-4.

Figure 1-3 Recording the action potential in the nerve fiber of the sensory neuron in the patellar stretch reflex. (a) A diagram of the recording configuration. A tiny microelectrode is inserted into the sensory nerve fiber, and a voltmeter is connected to measure the voltage difference (E) between the inside (a) and the outside (b) of the nerve fiber. (b) When the microelectrode penetrates the fiber, the resting membrane potential of the nerve fiber is measured. When the sensory neuron is activated by stretching the muscle, an action potential occurs and is recorded as a rapid shift in the recorded membrane potential of the sensory nerve fiber.

Figure 1-4 Chemical transmission mediates synaptic communication between cells in the patellar reflex. The flow diagram shows the sequence of events involved in the release of chemical neurotransmitter from the synaptic terminal.

Because signaling both within and between cells in the nervous system involves changes in the membrane potential, the brain is essentially an electrochemical organ. Therefore, to understand how the brain functions, we must first understand the electrochemical mechanisms that give rise to a transmembrane voltage in cells. The remaining chapters in Part I are devoted to the task of developing the basic chemical and physical principles required to comprehend how cells communicate in the nervous system. In Part II, we will then consider how these electrochemical principles are exploited in the nervous system for both long-distance communication via action potentials and local communication at synapses.

2 Composition of Intracellular and Extracellular Fluids

When we think of biological molecules, we normally think of all the special molecules that are unique to living organisms, such as proteins and nucleic acids: enzymes, DNA, RNA, and so on. These are the substances that allow life to occur and that give living things their special characteristics. Yet, if we were to dissociate a human body into its component molecules and sort them by type, we would find that these special molecules are only a small minority of the total. Of all the molecules in a human body, only about 0.25% fall within the category of these special biological molecules. Most of the molecules are far more ordinary. In fact, the most common molecule in the body is water. Excluding nonessential body fat, water makes up about 75% of the weight of a human body. Because water is a comparatively light molecule, especially when compared with massive protein molecules, this 75% of body weight translates into a staggering number of molecules of water. Thus, water molecules account for about 99% of all molecules in the body. The remaining 0.75% consists of other simple inorganic substances, mostly sodium, potassium, and chloride ions. In the first part of this book we will be concerned in large part with the mundane majority of molecules, the 99.75% made up of water and inorganic ions.

Why should we study these mundane molecules? Many enzymatic reactions involving the more glamorous organic molecules require the participation of inorganic cofactors, and most biochemical reactions within cells occur among substances that are dissolved in water. Nevertheless, most inorganic molecules in the body never participate in any biochemical reactions. In spite of this, a sufficient reason to study these inorganic substances is that cells could not exist and life as we know it would not be possible if cells did not possess mechanisms to control the distribution of water and ions across their membranes. The purpose of this chapter is to see why that is true and to understand the physical principles that underlie the ability of cells to maintain their integrity in a hostile physicochemical environment.

Intracellular and Extracellular Fluids

The water in the body can be divided into two compartments: intracellular and extracellular fluid. About 55% of the water is inside cells, and the remainder is outside. The extracellular fluid, or ECF, can in turn be subdivided into plasma, lymphatic fluid, and interstitial fluid, but for now we can lump all the ECF together into one compartment. Similarly there are subcompartments within cells, but it will suffice for now to treat cells as uniform bags of fluid. The wall that separates the intracellular and extracellular fluid compartments is the outer cell membrane, also called the plasma membrane of the cell.

Both organic and inorganic substances are dissolved in the intracellular and extracellular water, but the compositions of the two fluid compartments differ. Table 2-1 shows simplified compositions of ECF and intracellular fluid (ICF) for a typical mammalian cell. The compositions shown in the table are simplified by including only those substances that are important in governing the basic osmotic and electrical properties of cells. Many other kinds of inorganic and organic solutes beyond those shown in the table are present in both the ECF and ICF, and many of them have important physiological roles in other contexts. For the present, however, they can be ignored.

The principal cation (positively charged ion) outside the cell is sodium, although there is also a small amount of potassium, which will be important to consider when we discuss the origin of the membrane potential of cells. Inside cells, the situation is reversed, with a small amount of sodium and potassium being the principal cation. Negatively charged chloride ions, which are present at a high concentration in ECF, are relatively scarce in ICF. The major anion (negatively charged ion) inside cells is actually a class of molecules that bear a net negative charge. These intracellular anions, which we will abbreviate A–, include protein molecules, acidic amino acids like aspartate and glutamate, and inorganic ions like sulfate and phosphate. For the purposes of this book, the anions of this class outside cells can be ignored, and we will simplify the situation by assuming that the sole extracellular anion is chloride.

Table 2-1 Simplified compositions of intracellular and extracellular fluids for a typical mammalian cell.

It will also be important to consider the concentration of water on the two sides of the membrane, which is also shown in Table 2-1. It may seem odd to speak of the “concentration” of the solvent in ECF and ICF. However, as we shall see when we consider the maintenance of cell volume, the concentration of water must be the same inside and outside the cell, or water will move across the membrane and cell volume will change.

Another important consideration will be whether a particular substance can cross the plasma membraneathat is, whether the membrane is permeable to that substance. The plasma membrane is permeable to water, potassium, and chloride, but is effectively impermeable to sodium (however, we will reconsider the sodium permeability later). Of course, if the membrane is to do its job properly, it must keep the organic anions inside the cell; otherwise, all of a cell’s essential biochemical machinery would simply diffuse away into the ECF. Thus, the membrane is impermeable to A–.

As described in Chapter 1, there is an electrical voltage across the plasma membrane, with the inside of the cell being more negative than the outside. The voltage difference is usually about 60–100 millivolts (mV), and is referred to as the membrane potential of the cell. By convention, the potential outside the cell is called zero; therefore, the typical value of the membrane potential (abbreviated Em) is –60 to –100 mV, as shown in Table 2-1. A major concern of the first section of this book will be the origin of this electrical membrane potential. In later sections, we will discuss how the membrane potential influences the movement of charged particles across the cell membrane and how the electrical energy stored in the membrane potential can be tapped to generate signals that can be passed from one cell to another in the nervous system.

The Structure of the Plasma Membrane

Before we consider the mechanisms that allow cells to maintain the differences in ECF and ICF shown in Table 2-1, it will be helpful to look at the structure of the outer membrane of the cell, the plasma membrane. The control mechanisms responsible for the differences between ICF and ECF reside within the plasma membrane, which forms the barrier between the intracellular and extracellular compartments.

It has long been known that the contents of a cell will leak out if the cell is damaged by being poked or prodded with a glass probe. Also, some dyes will not enter cells when dissolved in the ECF, and the same dyes will not leak out when injected inside cells. These observations, first made in the nineteenth century, led to the idea that there is a selectively permeable barrier—the plasma membrane—separating the intracellular and extracellular fluids.

The first systematic observations of the kinds of molecules that would enter cells and the kinds that were excluded were made by Overton in the early part of the twentieth century. He found that, in general, substances that are highly soluble in lipids enter cells more easily than substances that are less soluble in lipids. Lipids are molecules that are not soluble in water or other polar solvents, but are soluble in oil or other nonpolar solvents. Thus, Overton suggested that the plasma membrane of a cell is made of lipids and that substances can cross the membrane if they can dissolve in the membrane lipids.

There were some exceptions to the general lipid solubility rule. Electrically charged substances, like potassium and chloride ions, are almost totally insoluble in lipids, yet they manage to cross the plasma membrane. Other substances, such as urea, entered cells more easily than expected from their lipid solubility alone. To take account of these exceptions, Overton suggested that the lipid membrane is shot through with tiny holes or pores that allow highly water soluble (hydrophilic) substances, such as ions, to cross the membrane. Only hydrophilic substances that are small enough to fit through these small aqueous pores can cross the membrane. Larger molecules like proteins and amino acids cannot fit through the pores and thus cannot cross the membrane without the help of special transport mechanisms.

The molecules of the lipid skin of cell membranes appear to be arranged in a layer only two molecules thick. Evidence for this arrangement was obtained from experiments in which the lipids were chemically extracted from the plasma membranes of cells and spread out on a trough of water in such a way that they formed a film only one molecule thick. When the area of this mono-layer “oil slick” was measured, it was found to be about twice the total surface area of the intact cells from which the lipids were obtained. This suggests that the membrane of the intact cells was two molecules thick. Such a membrane is called a lipid bilayer membrane.

The bilayer arrangement of the cell membrane makes chemical sense when we consider the characteristics of the particular lipid molecules found in the plasma membrane. The cell lipids are largely phospholipids, which are molecules that have both a polar region that is hydrophilic and a nonpolar region that is hydrophobic. When surrounded by water, these lipid molecules tend to aggregate, with the hydrophilic regions oriented outward toward the surrounding water and the hydrophobic regions pointed inward toward each other. When spread out in a sheet with water on each side of the sheet, the phospholipids can maintain their preferred state by forming a bimolecular sandwich, with the hydrophilic parts on the outside toward the water, and the hydrophobic parts in the middle, pointed toward each other. This bilayer model for the cell plasma membrane is illustrated in Figure 2-1.

Figure 2-1 also shows another important characteristic of cell membranes. They contain not only lipid molecules but also protein molecules. Some proteins are attached to the inner or outer surface of the cell membrane, and others penetrate all the way through the membrane so that they form a bridge from one side to the other. Some of these transmembrane proteins form the aqueous pores, or channels, that allow ions and other small hydrophilic molecules to cross the membrane. If we separate membranes from the rest of the cell and analyze their composition, we find that, by weight, only about one-third of the membrane material is lipid; most of the rest is protein. Thus, the lipids form the backbone of the membrane, but proteins are an important part of the picture. We will see later that the proteins are very important in controlling the movement of substances, particularly ions, across the cell membrane.

Figure 2-1 A schematic diagram of a section of the plasma membrane. The backbone of the membrane is a sheet of lipid molecules two molecules thick. Inserted into this sheet are various types of protein molecules. Some protein molecules extend all the way across the sheet, from the inner to the outer face. These transmembrane proteins sometimes form aqueous pores or channels through which small hydrophilic molecules, such as ions, can cross the membrane. The diagram shows two such channels; one is cut in cross-section to reveal the interior of the pore.

We can get an idea of the importance of membrane proteins for life by examining how much of the entire genome of a simple organism is taken up by genes encoding membrane proteins. One of the smallest genomes of any free-living organism is that of Mycoplasma genitalium, a microbe whose genome can be regarded as close to the minimum required for an independent, cellular life form. The DNA of M. genitalium has been completely sequenced, revealing a total of 482 individual genes. Of this total, 140 genes, or about 30%, code for membrane proteins. Thus, M. genitalium expends a large fraction of its total available DNA for the membrane proteins that sit at the interface between the microbe and its external environment. This points out the central role of these proteins in the maintenance of cellular life.

Anatomical evidence also supports the model shown in Figure 2-1. The cell membrane is much too thin to be seen with the light microscope. In fact, it is almost too thin to be seen with the electron microscope. However, with an electron microscope it is possible to see at the outer boundary of a cell a three-layered (trilaminar) profile like a railroad track, with a light central region separating two darker bands. Figure 2-2 is an example of an electron micrograph showing the plasma membranes of two cells lying in close contact. The interpretation of the trilaminar profile is that the two dark bands represent the polar heads of the membrane phospholipids and protein molecules on the inner and outer surfaces of the membrane and that the lighter region between the two dark bands represents the nonpolar tails of the lipid molecules. The total thickness of the sandwich is about 7.5 nm. The lighter-colored “fuzz” surrounding the trilaminar profiles of the two cell membranes in Figure 2-2 consists in part of portions of membrane-associated protein molecules extending out into the intracellular and extracellular spaces. The two cells shown in Figure 2-2 are nerve cells (neurons) in the brain, and the region of close contact is a specialized junction, called a synapse, where electrical activity is relayed from one nerve cell to another. The synapse is the basic mechanism of information transfer in the brain, and one of our major goals in this book is to understand how synapses work.

By using a special form of microscopy called freeze-fracture electron microscopy, it is possible to visualize more clearly the protein molecules that are embedded in the plasma membrane. A schematic representation of the freeze-fracture technique is shown in Figure 2-3. A small sample of the tissue to be examined is frozen in liquid nitrogen, and then a thin sliver of the frozen tissue is shaved off with a sharp knife. Because the tissue is frozen, however, the sliver is not so much sliced off as broken off from the sample. In some cases, like that shown in Figure 2-3, the line of fracture runs between the two lipid layers of the membrane bilayer, leaving holes where protein molecules are ripped out of the lipid monolayer and protrusions where membrane proteins are ripped out of the opposing monolayer and come along with the shaved sliver. An example of such a freeze-fracture sample viewed through the electron microscope is shown in Figure 2-4. The membrane proteins appear as small bumps in the otherwise smooth surface of the plasma membrane, like grains of sand sprinkled on a freshly painted surface. In the discussion of the transmission of signals at synapses in Chapter 8, we will see other examples of freeze-fracture electron micrographs and see how they can provide important evidence about the physiological functioning of cells.

Figure 2-2 High-power electron micrograph of the plasma membranes of two neighboring cells. Note the two dark bands separated by a light region at the outer surface of each cell. The two cells are nerve cells from the brain, and the point of close contact between them is a synapse, the point of information transfer in the nervous system. Note also the membrane-bound intracellular structures (labeled SV), called synaptic vesicles, inside one of the cells; the vesicle membranes also have the trilaminar profile seen in the plasma membranes. We will learn more about synaptic vesicles and synapses in Chapters 8 and 9. (Courtesy of A. L. deBlas of the University of Connecticut.)

Figure 2-3 Schematic illustration of the freeze-fracture procedure for electron microscopy. When a fracture line runs between the two lipid layers of the plasma membrane, some membrane proteins stay with one monolayer, others with the other layer. When the fractured surface is then examined with the electron microscope, the remaining proteins appear as protruding bumps in the surface.

Figure 2-4 Example of a fractured membrane surface containing protein molecules, viewed through the electron microscope. The membrane surface shown is that of the presynaptic nerve terminal at the nerve–muscle junction, which will be discussed in detail in Chapter 8. The protein molecules are the small bumps scattered about on the planar surface of the membrane. (Reproduced from C.-P. Ko, Regeneration of the active zone at the frog neuromuscular junction. Journal of Cell Biology 1984;98:1685–1695; by copyright permission of the Rockefeller University Press.)

Summary

The most common molecules in the body are water and simple inorganic molecules—mainly sodium, potassium, and chloride ions. The water in the body can be divided into two compartments: the intracellular and extracellular fluids. The barrier between those two compartments is the plasma membrane of the cell, which is a phospholipid bilayer with protein molecules inserted into it. The extracellular fluid is high in sodium and chloride, but low in potassium, while the intracellular fluid is low in sodium and chloride, but high in potassium. This difference is maintained and regulated by control mechanisms residing in the plasma membrane, which acts as a selectively permeable barrier permitting some substances to cross but excluding others.

3 Maintenance of Cell Volume

At an early stage of evolution, before the development of cells, life might well have been nothing more than a loose confederation of enzyme systems and self-replicating molecules. A major problem faced by such acellular systems must have been how to keep their constituent parts from simply diffusing away into the surrounding murk. The solution to this problem was the development of a cell membrane that was impermeable to the organic molecules. This was the origin of cellular life. However, the cell membrane, while solving one problem, brought with it a new problem: how to achieve osmotic balance. To see how this problem arises, it will be useful to begin with a review of solutions, osmolarity, and osmosis. We will then turn to an analysis of the cellular mechanisms used to deal with problems of osmotic balance.

Molarity, Molality, and Diffusion of Water

Examine the situation illustrated in Figure 3-1. We take 1 liter of pure water and dissolve some sugar in it. The dissolved sugar molecules take up some space that was formerly occupied by water molecules, and thus the volume of the solution increases. Recall that the concentration of a substance is defined as the number of molecules of that substance per unit volume of solution. In Figure 3-1, this means that the concentration of water in the sugar–water solution is lower than it was in the pure water before the sugar was dissolved. This is because the total volume increased after the sugar was added, but the total number of water molecules present is the same before and after dissolving the sugar in the water.

Figure 3-1 When sugar molecules (filled circles) are dissolved in a liter of water, the resulting solution occupies a volume greater than a liter. This is because the sugar molecules have taken up some space formerly occupied by water molecules (open circles). Therefore, the concentration of water (number of molecules of water per unit volume) is lower in the sugar–water solution.

To compare the concentrations of water in solutions containing different concentrations of dissolved substances, we will use the concept of osmolarity. A solution containing 1 mole of dissolved particles per liter of solution (a 1 molar, or 1 M, solution) is said to have an osmolarity of 1 osmolar (1 Osm), and a 1 millimolar (1 mM) solution has an osmolarity of 1 milliosmolar (1 mOsm). The higher the osmolarity of a solution, the lower the concentration of water. For practical purposes in biological solutions, it doesn’t matter what the dissolved particle is; that is, the concentration of water is effectively the same in a solution of 0.1 Osm glucose, 0.1 Osm sucrose, or 0.1 Osm urea. To be strictly correct in discussing the concentration of water in various solutions, we would have to speak of the molality, rather than the molarity, of the solutions. Whereas molarity is defined as moles of solute per liter of solution, molality is defined as moles of solute per kilogram of solvent. This definition means that molality takes into account the fact that solutes having a higher molecular weight displace more water per mole of solute than do solutes with a lower molecular weight. That is, a liter of solution containing 1 mole of a large molecule, like a protein, would contain less water (and hence fewer grams of water) than a liter of solution containing 1 mole of a small molecule, like urea. Thus, the molality of the protein solution would be higher than the molality of the urea solution, even though both solutions have the same molarity (1 M). For our purposes, however, it will be adequate to treat molarity and osmolarity as equivalent to molality and osmolality.

It is important in determining the osmolarity of a solution to take into account how many dissolved particles result from each molecule of the dissolved substance. Glucose, sucrose, and urea molecules don’t dissociate when they dissolve, and thus a 0.1 M glucose solution is a 0.1 Osm solution. A solution of sodium chloride, however, contains two dissolved particles—a sodium and a chloride ion—from each molecule of salt that goes into solution. Thus, a 0.1 M NaCl solution is a 0.2 Osm solution. To be strictly correct, we would have to take into account interactions among the ions in a solution, so that the effective osmolarity might be less than we would expect from assuming that all dissolved particles behave independently. But for dilute solutions like those we usually encounter in cell biology, such interactions are weak and can be safely ignored. Thus, for practical purposes we will assume that all dissolved particles act independently in determining the total osmolarity of a solution. Under this assumption, then, solutions containing 300 mM glucose, 150 mM NaCl, 100 mM NaCl + 100 mM glucose, or 75 mM NaCl + 75 mM KCl would all have the same total osmolarity — 300 mOsm.

When solutions of different osmolarity are placed in contact through a barrier that allows water to move across, water will diffuse across the barrier down its concentration gradient (that is, from the lower osmolar solution to the higher). This movement of water down its concentration gradient is called osmosis. Consider the example shown in Figure 3-2a, which shows a container divided into two equal compartments that are filled with glucose solutions. Imagine that the barrier dividing the container is made of an elastic material, so that it can stretch freely. If the barrier allows both water and glucose to cross, then water will move from side 1 to side 2, down its concentration gradient, and glucose will move from side 2 to side 1. The movement of water and glucose will continue until their concentrations on the two sides of the barrier are equal. Thus, side 1 gains glucose and loses water, and side 2 loses glucose and gains water until the glucose concentration on both sides is 150 mM. There will be no net change in the volume of solution on either side of the barrier, as shown in Figure 3-2b.

Figure 3-2 The effect of properties of the barrier separating two different glucose solutions on final volumes of the solutions. The starting conditions are shown in [a]. (b) If the barrier allows both glucose and water to cross, the volumes of the two solutions do not change when equilibrium is reached. (c) If the barrier allows only water to cross, osmolarities of the two solutions are the same at equilibrium, but the final volumes differ.

If the barrier in Figure 3-2a allows water but not glucose to cross, however, the outcome will be quite different from that shown in Figure 3-2b. Once again, water will move down its concentration gradient from side 1 to side 2. In this case, though, the loss of water will not be compensated by a gain of glucose. As water continues to leave side 1 and accumulates on side 2, the volume of side 2 will increase and the volume of side 1 will decrease. The accumulating water will exert a pressure on the elastic barrier, causing it to expand to the left to accommodate the volume changes (as shown in Figure 3-2c). The resulting volume changes will increase the osmolarity of side 1 and decrease the osmolarity of side 2, and this process will continue until the osmolarities of the two sides are equal—150 mOsm. In order to prevent the changes in volume, we would have to exert a pressure against the elastic barrier from side 1 to keep it from stretching. This pressure would be equal to the pressure moving water down its concentration gradient and would provide a measure of the osmotic pressure across the barrier.

Figure 3-3 A simple model cell containing organic molecules, P. The ECF is a solution of solute, S, in water. Both water and S can cross the cell membrane, but P cannot.

Osmotic Balance and Cell Volume

Return now to the hypothetical primitive cell, early after the development of a cell membrane. In order for the cell membrane to do its job, it must be impermeable to the organic molecules inside the cell. But if the compositions of the extracellular and intracellular fluids are the same, with the exception of the internal organic molecules, the cell faces an imbalance of water on the two sides of the membrane. This situation is shown schematically in Figure 3-3. Here, the solutes that are in common in ICF and ECF are grouped together and symbolized by S. The extra solute inside the cell—the organic molecules (symbolized by P, for protein)—cause the concentration of water inside the cell to be less than it is outside. Put another way, the total osmolarity inside the cell is greater than it is outside the cell. There are two solutes inside, S and P, and only one outside. Water will therefore enter the cell and will continue to enter until the osmolarity on the two sides of the membrane is the same. Because the volume of the sea is essentially infinite relative to the volume of a cell and can thus be treated as constant, this end point could be reached only when the internal concentration of organic solutes is zero. This would require the volume of the cell to be infinite. Real cell membranes are not infinitely elastic, and thus water will enter the cell, causing it to swell, until the membrane ruptures and the cell bursts.

It will be convenient to summarize this situation in equation form. If a substance is at diffusion equilibrium across a cell membrane, there is no net movement of that substance across the membrane. For any solute, S, that can cross the cell membrane, this diffusion equilibrium will be reached when

(3-1)

The square brackets indicate the concentration of a substance, and the subscripts i and o refer to the inside and outside of the cell. Thus, in order for water to be at equilibrium, we would expect that

(3-2)

which is the same as saying that at equilibrium, the total osmolarity inside the cell must be the same as the total osmolarity outside the cell. For the cell of Figure 3-3, diffusion equilibrium will be reached only when the concentrations of all substances that can cross the membrane (in this case, S and water) are the same inside and outside the cell. This would require that Equations (3-1) and (3-2) be true simultaneously, which can occur only if [P]i is zero.

Answers to the Problem of Osmotic Balance

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