4

CHAPTER
Movement of Solutes and Water
Across Cell Membranes

4.1 Diffusion
4.2 Mediated-Transport Systems
4.3 Osmosis
4.4 Endocytosis and Exocytosis
4.5 Epithelial Transport
Chapter 4 Clinical Case Study

Changes in red blood cell shape due to osmosis; the knobby appearance of
some cells is due to water leaving the cell. VVG/Science Photo Library/Science Source

Y
ou learned in Chapter 3 that the contents of a cell are separated
from the surrounding extracellular fluid by a thin bilayer of lipids
and protein, which forms the plasma membrane. You also learned
that membranes associated with mitochondria, endoplasmic reticulum,
lysosomes, the Golgi apparatus, and the nucleus divide the intracellular
fluid into several membrane-bound compartments. The movements of
molecules and ions between the various cell organelles and the cytosol,
and between the cytosol and the extracellular fluid, depend on the
properties of these membranes. The rates at which different substances
move through membranes vary considerably and in some cases can be
controlled—increased or decreased—in response to various signals.
This chapter focuses upon the transport functions of membranes, with
emphasis on the plasma membrane. The controlled movement of solutes
such as ions, glucose, and gases, as well as the movement of water across
membranes, is of profound importance in physiology. As just a few
examples, such transport mechanisms are essential for cells to maintain
their size and shape, energy balance, and their ability to send and respond
to electrical or chemical signals from other cells.
As you read the first section, think how diffusion is a good example
of the general principle of physiology introduced in Chapter 1, that
physiological processes are dictated by the laws of chemistry and physics.
In the subsequent sections, consider how the general physiological
principles of homeostasis and of controlled exchange of materials apply. ■
95
4.1 Diffusion from the left to the right side of the solution shown in Figure 4.1a is
greater than that of the reverse direction, simply because there are
One of the fundamental physical features of molecules of any sub- initially more molecules on the left side. At equilibrium, the mole-
stance, whether solid, liquid, or gas, is that they are in a continu- cules continue to randomly move but do so equally in all directions.
ous state of movement or vibration. The energy for this movement Many processes in living organisms are closely associated
comes from heat; the warmer a substance is, the faster its mol- with simple diffusion. For example, oxygen, nutrients, and other
ecules move. In solutions, such rapidly moving molecules cannot molecules enter and leave the smallest blood vessels (capillaries)
travel very far before colliding with other molecules, undergo- by simple diffusion, and the movement of many substances across
ing millions of collisions every second. Each collision alters the plasma membranes and organelle membranes occurs by simple
direction of the molecule’s movement, so that the path of any one diffusion. In this way, simple diffusion is one of the key mecha-
molecule becomes unpredictable. Because a molecule may at any nisms by which cells maintain homeostasis. For the remainder of
instant be moving in any direction, such movement is random, the text, we will often follow convention and refer only to “diffu-
with no preferred direction of movement. sion” when describing simple diffusion. You will learn later about
The random thermal motion of molecules in a liquid or another type of diffusion called facilitated diffusion.
gas will eventually distribute them uniformly throughout a con-
tainer. This is the second law of thermodynamics, which states Magnitude and Direction of Diffusion
that a closed (isolated) system will always tend toward maximum Figure 4.2 illustrates the diffusion of glucose between two com-
entropy, or disorder. Thus, if we start with a solution in which a sol- partments of equal volume separated by a permeable barrier. Ini-
ute is more concentrated in one region than another (Figure 4.1a), tially, glucose is present in compartment 1 at a concentration of
random thermal motion will redistribute the solute from regions 20 mmol/L, and there is no glucose in compartment 2. The ran-
of higher concentration to regions of lower concentration until the dom movements of the glucose molecules in compartment 1 move
solute reaches a uniform concentration throughout the solution some of them into compartment 2. The amount of material cross-
(Figure 4.1b). This movement of molecules from one location to ing a surface in a unit of time is known as a flux. This one-way
another solely as a result of their random thermal motion is known flux of glucose from compartment 1 to compartment 2 depends
as simple diffusion. An important feature of simple diffusion on the concentration of glucose in compartment 1. If the number
is that it requires no energy other than heat—that is, it does not of molecules in a unit of volume is doubled, the flux of molecules
require ATP derived from metabolism. across the surface of the unit will also be doubled because twice as
Key to your understanding of this process is recognizing many molecules will be moving in any direction at a given time.
that molecules do not move in a purposeful way; their movement After a short time, some of the glucose molecules that have
is entirely random. The probability that more molecules will move entered compartment 2 will randomly move back into compart-
ment 1 (see Figure 4.2, time B). The magnitude of the glucose
flux from compartment 2 to compartment 1 depends upon the
concentration of glucose in compartment 2 at any time.
The net flux of glucose between the two compartments at
any instant is the difference between the two one-way fluxes. The
net flux determines the net gain of molecules in compartment
2 per unit time and the net loss from compartment 1 per unit time.
Eventually, the concentrations of glucose in the two compart-
ments become equal at 10 mmol/L. Glucose molecules continue
to move randomly, and some will find their way from one compart-
(a) Molecules diffusing
ment to the other. However, the two one-way fluxes are now equal
in magnitude but opposite in direction; therefore, the net flux of glu-
cose is zero (see Figure 4.2, time C). The system has now reached
diffusion equilibrium. No further change in the glucose concentra-
tions of the two compartments will occur because of the equal rates
of diffusion of glucose molecules in both directions between the
two compartments.
Several important properties of diffusion can be empha-
sized using this example. Three fluxes can be identified—the two
one-way fluxes occurring in opposite directions from one com-
partment to the other, and the net flux, which is the difference
between them (Figure 4.3). The net flux is the most important
(b) Molecules at equilibrium component in diffusion because it is the net rate of material trans-
fer from one location to another. Although the movement of indi-
Figure 4.1 Simple diffusion. (a) Molecules initially
concentrated in one region of a solution will, due to random thermal vidual molecules is random, the net flux is always greater from
motion, undergo net diffusion from the region of higher concentration regions of higher concentration to regions of lower concentration.
to the region of lower concentration. (b) With time, the molecules will For this reason, we often say that substances move “downhill” by
become uniformly distributed throughout the solution—that is, the diffusion. The greater the difference in concentration between any
system will achieve maximum entropy. two regions, the greater the magnitude of the net flux. Therefore,
96 Chapter 4
 1 2 1 2 1 2
■ T
 he medium through which the molecules
are moving: Molecules diffuse more
rapidly in air than in water. This is because
collisions are less frequent in a gas phase.

Time A Time B Time C

Diffusion Rate Versus Distance
The distance over which molecules diffuse is
20 an important factor in determining the rate at
which they can reach a cell from the blood or
move throughout the interior of a cell after cross-
Glucose concentration (mmol/L)

ing the plasma membrane. Although individual

molecules travel at high speeds, the number of
Compartment 1 collisions they undergo prevents them from trav-
eling very far in a straight line. Diffusion times
10 increase in proportion to the square of the dis-
tance over which the molecules diffuse.
Compartment 2 Thus, although diffusion equilibrium can
be reached rapidly over distances of cellular
dimensions, it takes a very long time when dis-
tances of a few centimeters or more are involved.
For an organism as large as a human being, the
0 diffusion of oxygen and nutrients from the body
A B C
surface to tissues located only a few centimeters
Time below the surface would be far too slow to provide
adequate nourishment. This is overcome by the
Figure 4.2 Diffusion of glucose between two compartments of equal volume circulatory system, which provides a mechanism
separated by a barrier permeable to glucose. Initially, at time A, compartment 1 contains for rapidly moving materials over large distances
glucose at a concentration of 20 mmol/L and no glucose is present in compartment 2. At using a pressure source (the heart). This process,
time B, some glucose molecules have moved into compartment 2 and some of these are
known as bulk flow, is described in Chapter 12.
moving back into compartment 1. The length of the arrows represents the magnitudes of the
Diffusion, on the other hand, provides movement
one-way movements. At time C, diffusion equilibrium has been reached, the concentrations
of glucose are equal in the two compartments (10 mmol/L), and the net movement is zero. over the short distances between the blood, inter-
In the graph at the bottom of the figure, the green line represents the concentration in stitial fluid, and intracellular fluid.
compartment 1, and the purple line represents the concentration in compartment 2. Note
that at time C, glucose concentration is 10 mmol/L in both compartments. At that time, Diffusion Through Membranes
diffusion equilibrium has been reached. Up to now, we have considered general features
of diffusion of solutes in water. In living tissue,
DIG DEEPER however, diffusion often occurs across cellular
■ Imagine that at time C additional glucose could be added to compartment 1 such that
membranes, including between intracellular and
its concentration was instantly increased to 15 mmol/L. What would the graph look extracellular fluid compartments. For example,
like following time C? Draw the new graph on the figure and indicate the glucose cellular waste products of metabolism diffuse
concentrations in compartments 1 and 2 at diffusion equilibrium. (Note: It is not outward from cells, whereas nutrients diffuse
actually possible to instantly change the concentration of a substance in this way into cells; in both cases, the solutes must cross
because it will immediately begin diffusing to the other compartment as it is added.) the plasma membrane. What effects do mem-
Answer found in Appendix A. branes have on diffusion?
The rate at which a substance diffuses
across a plasma membrane can be measured
the concentration difference determines both the direction and the
by monitoring the rate at which its intracellular concentration
magnitude of the net flux.
approaches diffusion equilibrium with its concentration in the
At any concentration difference, however, the magnitude of
extracellular fluid. For simplicity’s sake, assume that because
the net flux depends on several additional factors:
the volume of extracellular fluid is large, its solute concentra-
■■ Temperature: The more elevated the temperature, the greater tion will remain essentially constant as the substance diffuses
the speed of molecular movement and the faster the net flux. into the fluid within a single cell (Figure 4.4). As with all
■■ Mass of the molecule: Large molecules such as proteins have diffusion processes, the net flux of material across the mem-
a greater mass and move more slowly than smaller molecules brane is from the region of greater concentration (the extracel-
such as glucose and, consequently, have a slower net flux. lular solution in this case) to the region of lower concentration
■■ Surface area: The greater the surface area separating two (the intracellular fluid). The magnitude of the net flux (that
regions, the greater the space available for diffusion and, is, the rate of diffusion J) is directly proportional to the dif-
therefore, the faster the net flux. ference in concentration across the membrane (Co − Ci, where
Movement of Solutes and Water Across Cell Membranes 97
 Compartment 1 Compartment 2
High solute concentration Low solute concentration
C o = constant extracellular concentration

One-way flux

Concentration
C i = Co

One-way flux
C i = intracellular concentration

Net flux

Time

Figure 4.3 The two one-way fluxes occurring during simple Figure 4.4 The increase in intracellular concentration as a solute
diffusion of solute across a boundary and the net flux (the difference diffuses from a constant extracellular concentration until diffusion
between the two one-way fluxes). The net flux always occurs in the equilibrium (Ci = Co) is reached across the plasma membrane of a cell.
direction from higher to lower concentration. Lengths of arrows indicate
magnitude of the flux.
containing an ionized phosphate group; therefore, they have a
o and i stand for concentrations outside and inside the cell), the low solubility in the lipid bilayer. Most of these substances are
surface area of the membrane A, and the membrane permeabil- retained within cells and organelles because they cannot diffuse
ity coefficient P as described by a modified form of Fick’s first across the lipid bilayer of membranes, unless the membrane con-
law of diffusion applied to biological membranes: tains special proteins such as ion channels, as we see next. The
J = PA(Co − Ci) relationship between the hydrophobicity of diffusing substances
and the chemical nature of lipid bilayers is an excellent example
The numerical value of the permeability coefficient P is an of the general principle of physiology that physiological processes
experimentally determined number for a particular type of molecule are dictated by the laws of chemistry and physics.
at a given temperature; it reflects the ease with which the molecule is
able to move through a given membrane. In other words, the greater Diffusion of Ions Through Ion Channels
the permeability coefficient, the faster the net flux across the mem- Ions such as Na+, K+, Cl−, and Ca2+ diffuse across plasma mem-
brane is for any given concentration difference and membrane surface branes at much faster rates than would be predicted from their
area. Depending on the magnitude of their permeability coefficients, very low solubility in membrane lipids. Also, different cells have
molecules typically diffuse a thousand to a million times slower quite different permeabilities to these ions, whereas nonpolar sub-
through membranes than through a water layer of equal thickness. stances have similar permeabilities in nearly all cells. Moreover,
Membranes, therefore, act as barriers that considerably slow the dif- artificial lipid bilayers containing no protein are practically imper-
fusion of molecules across their surfaces. The major factor limiting meable to these ions; this indicates that the protein component of
diffusion across a membrane is its chemical composition, namely the the membrane is responsible for these permeability differences.
hydrophobic interior of its lipid bilayer, as described next. You learned in Chapter 3 that integral membrane pro-
teins can span the lipid bilayer. Some of these proteins form
Diffusion Through the Lipid Bilayer ion channels that allow ions to diffuse across the membrane.
When the permeability coefficients of different organic mol- A single protein may have a conformation resembling that of a
ecules are examined in relation to their molecular structures, doughnut, with the hole in the middle providing the channel for
a correlation emerges. Whereas most polar molecules diffuse into ion movement. More often, several polypeptides aggregate, each
cells very slowly or not at all, nonpolar molecules diffuse much forming a subunit of the borders of a channel (Figure 4.5). The
more rapidly across plasma membranes—that is, they have large diameters of ion channels are very small, only slightly larger
permeability coefficients. The reason is that nonpolar molecules than those of the ions that pass through them. The small size of
can dissolve in the nonpolar regions of the membrane occupied the channels prevents larger molecules from entering or leaving.
by the fatty acid chains of the membrane phospholipids. An important characteristic of ion channels is that they can
In contrast, polar molecules have a much lower solubility show selectivity for the type of ion or ions that can diffuse through
in the membrane lipids. Increasing the lipid solubility of a sub- them. This selectivity is based on the channel diameter, the charged
stance by decreasing the number of polar or ionized groups it and polar surfaces of the polypeptide subunits that form the channel
contains will increase the number of molecules dissolved in the walls and electrically attract or repel the ions, and the number of
membrane lipids. This will increase the flux of the substance water molecules associated with the ions (so-called waters of hydra-
across the membrane. tion). For example, some channels (K+ channels) allow only potas-
Oxygen, carbon dioxide, fatty acids, and steroid hormones sium ions to pass, whereas others are specific for sodium ions (Na+
are examples of nonpolar molecules that diffuse rapidly through channels). For this reason, two membranes that have the same per-
the lipid portions of membranes. Most of the organic molecules meability to K+ because they have the same number of K+ channels
that make up the intermediate stages of the various metabolic may nonetheless have quite different permeabilities to Na+ if they
pathways (Chapter 3) are ionized or polar molecules, often contain different numbers of Na+ channels.
98 Chapter 4
Ion Movement and Membrane Potential is that like charges repel each other, and opposite charges attract
Thus far, we have described the direction and magnitude of solute each other. The excess negative charges inside the cell attract posi-
diffusion across a membrane in terms of the solute’s concentration tive charges outside the cell. The opposite charges tend to align
difference across the membrane, its solubility in the membrane themselves along the surfaces of the plasma membrane. This cre-
lipids, the presence of membrane ion channels, and the area of the ates an electrical potential across the membrane, the magnitude of
membrane. When describing the diffusion of ions, because they which is measured in units called millivolts.
are charged, one additional factor must be considered: the pres- The membrane potential provides an electrical force that
ence of electrical forces acting upon the ions. can influence the movement of ions through their channels across
A separation of electrical charge exists across plasma mem- a plasma membrane. For example, if the inside of a cell has a net
branes of most cells. This is known as a membrane ­potential negative charge with respect to the outside, as is generally true,
(Figure 4.6). The origin of a membrane potential will be described there will be an electrical force attracting positive ions into the
in detail in Chapter 6 in the context of neuronal function. Briefly, cell and repelling negative ions. Consequently, the direction and
it arises from an imbalance in electrical charges (ions) on either magnitude of ion fluxes across membranes depend on both the
side of the plasma membrane, such that a slight excess of negative concentration difference and the electrical difference (the mem-
charge exists within the cell. A fundamental principle of physics brane potential). These two driving forces are considered together
as a single, combined ­electrochemical gradient across a mem-
brane. As you will learn in subsequent chapters, the membrane
potential is the basis for the regulated flux of ions across mem-
branes, as occurs for example when Ca2+ enters the cytosol of a
muscle cell and triggers contraction of the cell. It also is the basis
for electrical communication between neurons.
The two forces that make up the electrochemical gradient
1 2 3 4 may in some cases oppose each other. For example, the membrane
potential may be driving K+ in one direction across the membrane
while the concentration difference for K+ favors flux of these ions
in the opposite direction. The net movement of K+ in this case
would be determined by the relative magnitudes of the two oppos-
ing forces—that is, by the electrochemical gradient across the
membrane.
(a) Two-dimensional view of a channel subunit in a membrane

Figure 4.5 Model of an ion channel composed of

five polypeptide subunits. Individual amino acids are
1 represented as beads. (a) A channel subunit consisting
2 4
3 of an integral membrane protein containing four
transmembrane segments (1, 2, 3, and 4), each of which
has an alpha-helical configuration within the membrane.
Although this model has only four transmembrane
Subunit
segments, some channel proteins have as many as 12.
(b) The same subunit as in (a) shown in three dimensions
(b) Three-dimensional view of folded channel subunit within the membrane, with the four transmembrane helices
aggregated together and shown as cylinders. (c) The ion
Ion channel channel consists of five of the subunits illustrated in (b),
which form the sides of the channel. As shown in cross
section, the helical transmembrane segment 2 (light purple)
of each subunit forms each side of the channel opening.
The presence of ionized amino acid side chains along this
region determines the selectivity of the channel to ions.
Although this model shows the five subunits as identical,
many ion channels are formed from the aggregation of
several different types of subunit polypeptides.
Cross section
viewed from above DIG DEEPER
Subunit ■ In Chapter 2, you learned that proteins have several
Aqueous pore levels of structure. Which levels of structures are
of ion channel 1 2 evident in the drawing of the ion channel in this
4 3 figure?
Subunit
Answer found in Appendix A.
(c) Ion channel with five subunits
Movement of Solutes and Water Across Cell Membranes 99
 like this is called a ligand (see Chapter 3). Such channels are there-
Extracellular fluid fore termed ligand-gated ion channels, and the ligands that influ-
+ Plasma
+
–
+
membrane ence them are often chemical messengers, such as those released
+ – – +
– – from the ends of neurons onto target cells. Second, changes in
+ +
– –
+ + the membrane potential can cause movement of certain charged
– Intracellular fluid –
+ + regions on a channel protein, altering its shape—these are
– –
+ + voltage-gated ion channels. Third, physically deforming (stretch-
+ – –
+
– – + ing) the membrane may affect the conformation of some channel
+
– Nucleus – + proteins—these are mechanically gated ion channels.
+ – – + A single type of ion may pass through several different types
+ – – + of channels. For example, a membrane may contain ligand-gated
+ –
– + K+ channels, voltage-gated K+ channels, and mechanically
– +
+ – – –+ gated K+ channels. The functions of these gated ion channels in
+ – –+ cell communication and electrical activity will be discussed in
+ – – – – –+
+ + + + Chapters 5 through 7, 9, and 12.

St udy and Review 4.1

Figure 4.6 The separation of electrical charge across a plasma
membrane (the membrane potential) provides the electrical force that ■ Simple diffusion: the movement of molecules from one
tends to drive positive ions (+) into a cell and negative ions (−) out.
location to another by random thermal motion
∙∙ Net flux: the difference between two one-way fluxes of a solute
Regulation of Diffusion Through Ion Channels
∙∙ Diffusion equilibrium: reached when the concentrations of a
Ion channels can exist in an open or closed state (Figure 4.7), and diffusing substance in two compartments become equal
changes in a membrane’s permeability to ions can occur rapidly as
these channels open or close. The process of opening and closing ■ Fick’s first law of diffusion: The magnitude of the net flux of
a substance across a membrane is directly proportional to the
ion channels is known as channel gating, like the opening and
concentration difference across the membrane, the surface area
closing of a gate in a fence. A single ion channel may open and of the membrane, and the membrane permeability coefficient.
close many times each second, suggesting that the channel protein
fluctuates between these conformations. Over an extended period ■ Nonpolar molecules: dissolve in lipid bilayer; readily diffuse
of time, at any given electrochemical gradient, the total number of through membranes
ions that pass through a channel depends on how often the channel ■ Ions diffuse across membranes through ion channels that are
opens and how long it stays open. transmembrane proteins.
Three factors can alter the channel protein conformations, ∙∙ Diffusion can be altered by opening or closing ion channels
producing changes in how long or how often a channel opens. First, (“channel gating”); this includes ligand-gated, voltage-gated,
the binding of specific molecules to channel proteins may directly and mechanically gated channels.
or indirectly produce either an allosteric or covalent change in the ■ Membrane potential: separation of electrical charge across a
shape of the channel protein. A molecule that binds to a protein plasma membrane
∙∙ arises due to an imbalance of ions across the membrane, such
Intracellular fluid that a slight excess of negative charge exists inside cells
Channel proteins Lipid bilayer ∙∙ combination of a membrane potential and a difference
in ion concentrations across a membrane creates an
electrochemical gradient for an ion across the membrane
Review Question: Imagine a nonpolar molecule that crosses a
plasma membrane and enters a cell. What factors might increase
its rate of diffusion? What might happen to the rate of diffusion
into the cell if a molecule was metabolized (used up or destroyed)
as soon as it entered the cell? (Answer found in Appendix A.)

Open ion channel Closed ion channel 4.2 Mediated-Transport Systems

Extracellular fluid
A general principle of physiology is that controlled exchange of
materials occurs between compartments and across cellular mem-
Figure 4.7 As a result of conformational changes in the proteins
forming an ion channel, the channel may be open, allowing ions to branes. Although diffusion through gated ion channels accounts for
diffuse across the membrane, or may be closed. The conformational some of the controlled transmembrane movement of ions, it does not
change is grossly exaggerated for illustrative purposes. The actual account for all of it. Moreover, a number of other molecules, includ-
conformational change is more likely to be just sufficient to allow or ing amino acids and glucose, are able to cross membranes yet are
prevent an ion to fit through. too polar to diffuse through the lipid bilayer and too large to diffuse
100 Chapter 4
 Intracellular fluid

Figure 4.8 Highly schematic model of

mediated transport. A change in the conformation
of the transporter exposes the transporter binding
site first to one surface of the membrane then to
the other, thereby transferring the bound solute
from one side of the membrane to the other. This
model shows net mediated transport from the
extracellular fluid to the inside of the cell. In
Transporter Binding site many cases, the net transport is in the opposite
protein
direction. The size of the conformational change
Transported solute is exaggerated for illustrative purposes in this and
Extracellular fluid
subsequent figures.

through channels. The passage of these molecules and the nondif- The flux through a mediated-transport system can be altered by
fusional movements of ions are mediated by integral membrane pro- changing any of these four factors.
teins known as transporters. The movement of substances through a For any transported solute, a finite number of specific trans-
membrane by any of these mechanisms is called mediated transport, porters reside in a given membrane at any particular moment. As with
which depends on conformational changes in these transporters. any binding site, as the concentration of the solute to be transported
The transported solute must first bind to a specific is increased, the number of occupied binding sites increases until
site on a transporter protein, a site exposed to the solute on the transporters become saturated—that is, until all the binding sites
one surface of the membrane (Figure 4.8). A portion of the are occupied. When the transporter binding sites are saturated, the
transporter then undergoes a change in shape, exposing this maximal flux across the membrane has been reached and no further
same binding site to the solution on the opposite side of the mem- increase in solute flux will occur with increases in solute concentration.
brane. The dissociation of the substance from the transporter bind- Contrast the solute flux resulting from mediated transport
ing site completes the process of moving the material through the with the flux produced by diffusion through the lipid portion of
membrane. Using this mechanism, molecules can move in either a membrane (Figure 4.9). The flux due to diffusion increases in
direction, getting on the transporter on one side and off at the other.
Many of the characteristics of transporters and ion chan-
nels are similar. Both involve membrane proteins and show Diffusion
chemical specificity. They do, however, differ in the number
of molecules or ions crossing the membrane by way of these
membrane proteins. Ion channels typically move several thou-
sand times more ions per unit time than molecules moved by
Flux into cell

transporters. In part, this is because a transporter must change

its shape for each molecule transported across the membrane,
whereas an open ion channel can support a continuous flow of Maximal flux
ions without a change in conformation. Imagine, for example,
how many more cars can move over a bridge than can be shuttled
back and forth by a ferry.
Many types of transporters are present in membranes, Mediated transport
each type having binding sites that are specific for a particular
substance or a specific class of related substances. For example,
although amino acids and sugars undergo mediated transport, a Extracellular solute concentration
protein that transports amino acids does not transport sugars, and
vice versa. Just as with ion channels, the plasma membranes of Figure 4.9 The flux of molecules diffusing into a cell across
different cells contain different types and numbers of transport- the lipid bilayer of a plasma membrane (green line) increases
ers; consequently, they exhibit differences in the types of sub- continuously in proportion to the extracellular concentration, whereas
stances transported and in their rates of transport. the flux of molecules through a mediated-transport system (purple
Four factors determine the magnitude of solute flux through line) reaches a maximal value.
a mediated-transport system:
■■ the solute concentration DIG DEEPER
■■ the affinity of the transporters for the solute ■ What might determine the value for maximal flux of a mediated-
■■ the number of transporters in the membrane transport system as shown here?
■■ the rate at which the conformational change in the transport Answer found in Appendix A.
protein occurs
Movement of Solutes and Water Across Cell Membranes 101
direct proportion to the increase in extracellular concentration, and Low concentration High concentration
there is no limit because diffusion does not involve binding to a fixed Membrane
number of sites. (At very high ion concentrations, however, diffu-
sion through ion channels may approach a limiting value because of
the fixed number of channels available, just as an upper limit deter-
mines the rate at which cars can move over a bridge.)
When transporters are saturated, however, the maximal
transport flux depends upon the rate at which the conformational Simple diffusion
changes in the transporters can transfer their binding sites from
one surface to the other. This rate is much slower than the rate of
ion diffusion through ion channels.
Thus far, we have described mediated transport as though
all transporters had similar properties. In fact, two types of medi-
ated transport exist—facilitated diffusion and active transport.

Facilitated Diffusion
Facilitated diffusion
As in simple diffusion, in facilitated diffusion the net flux of a
molecule across a membrane always proceeds from higher to lower
concentration, or “downhill” across a membrane. The key differ-
ence between these two processes is that facilitated diffusion uses
a transporter to move solute, as in Figure 4.8. Net facilitated dif-
fusion continues until the concentrations of the solute on the two
sides of the membrane become equal. At this point, equal numbers
of molecules are binding to the transporter at the outer surface of Active transport
the cell and moving into the cell as are binding at the inner surface
and moving out. Neither simple diffusion nor facilitated diffusion Figure 4.10 Direction of net solute flux crossing a membrane by
is directly coupled to energy (ATP) derived from metabolism. For simple diffusion (high to low concentration), facilitated diffusion (high
this reason, they are incapable of producing a net flux of solute to low concentration), and active transport (low to high concentration).
from a lower to a higher concentration across a membrane. The colored circles represent transporter molecules.
Among the most important facilitated-diffusion systems in
the body are those that mediate the transport of glucose across
thermodynamics because it creates less disorder. It can be achieved
plasma membranes. Without such glucose transporters, or GLUTs
only with continuous input of energy into the active-transport pro-
as they are abbreviated, cells would be virtually impermeable to
cess. Two means of coupling energy to transporters are known:
glucose, which is a polar molecule. It might be expected that as
(1) the direct use of ATP in primary active transport, and (2) the
a result of facilitated diffusion the glucose concentration inside
use of an electrochemical gradient across a membrane to drive the
cells would become equal to the extracellular concentration. This
process in secondary active transport.
does not occur in most cells, however, because glucose is metabo-
lized in the cytosol to glucose 6-phosphate almost as quickly as it Primary Active Transport
enters (refer back to Figure 3.42). Consequently, the intracellular
The hydrolysis of ATP by a transporter provides the energy for pri-
glucose concentration remains lower than the extracellular con-
mary active transport. The transporter itself is an enzyme called
centration, and there is a continuous net flux of glucose into cells.
ATPase that catalyzes the breakdown of ATP and, in the process,
In later chapters, you will learn that the number of GLUT mol-
phosphorylates itself. Phosphorylation of the transporter protein is
ecules in the plasma membranes of many cells can be regulated by
a type of covalent modulation that changes the conformation of the
the endocrine system. In this way, facilitated diffusion contributes
transporter and the affinity of the transporter’s solute binding site.
significantly to metabolic homeostasis.
One of the best-studied examples of primary active transport
Active Transport is the movement of sodium and potassium ions across plasma mem-
branes by the Na+/K+-ATPase pump. This transporter, which is
Active transport differs from facilitated diffusion in that energy
present in all cells, moves Na+ from intracellular to extracellular
is used to move a substance uphill across a membrane—that is,
fluid, and K+ in the opposite direction. In both cases, the movements
against the substance’s concentration gradient (Figure 4.10). As
of the ions are against their respective concentration gradients.
with facilitated diffusion, active transport requires a substance to
Figure 4.11 illustrates the sequence the Na+/K+-ATPase
bind to the transporter in the membrane. Because these transporters
pump is believed to use to transport these two ions in opposite
move the substance uphill, they are often referred to as pumps. As
directions:
with facilitated-diffusion transporters, active-transport transporters
exhibit specificity and saturation—that is, the flux via the trans- 1 Initially, the transporter, with an associated molecule of
porter is maximal when all transporter binding sites are occupied. ATP, binds three sodium ions at high-affinity sites on the
The net movement of solute from lower to higher concen- intracellular surface of the protein. Two binding sites also
tration and the maintenance of a higher steady-state concentra- exist for K+, but at this stage they are in a low-affinity state
tion on one side of a membrane is counter to the second law of and therefore do not bind intracellular K+.
102 Chapter 4
 High K+
3 Na+
1 2 3

+
Intracellular fluid ADP

Low Na+
ATP Bound phosphate

Low K+
High Na+
3 Na+
Extracellular fluid

4 5

2 K+
Released phosphate
ATP

2 K+

Figure 4.11 Active transport of Na+ and K+ mediated by the Na+/K+-ATPase pump. See text for the numbered sequence of events occurring
during transport.

2 Binding of Na+ results in activation of an inherent ATPase sodium ions out of a cell and two potassium ions into a cell. This
activity of the transporter protein, causing phosphorylation results in a net transfer of positive charge to the outside of the cell;
of the cytosolic surface of the transporter and releasing a therefore, this transport process is not electrically neutral and as
molecule of ADP.
3 Phosphorylation results in a conformational change of the
transporter, exposing the bound Na+ to the extracellular fluid Extracellular fluid
and, at the same time, reducing the affinity of the binding
Intracellular fluid
sites for Na+. The Na+ is released from its binding sites.
Na+ 145 mM
4 The new conformation of the transporter results in an Na+ 15 mM
increased affinity of the two binding sites for K+, allowing K+ 5 mM
K+ 150 mM
two K+ to bind to the transporter on the extracellular surface.
5 Binding of K+ results in dephosphorylation of the ATP
transporter. This returns the transporter to its original
Na+/K+ -ATPase 3 Na+
conformation, resulting in reduced affinity of the K+
binding sites and increased affinity of the Na+ binding 2 K+
sites. K+ is therefore released into the intracellular fluid, ADP
allowing additional Na+ (and ATP) to be bound at the
intracellular surface.
The pumping activity of the Na+/K+-ATPase primary
Figure 4.12 The primary active transport of sodium and
active transporter establishes and maintains the characteristic dis- potassium ions in opposite directions by the Na+/K+-ATPase in plasma
tribution of high intracellular K+ and low intracellular Na+ relative membranes is responsible for the low Na+ and high K+ intracellular
to their respective extracellular concentrations (Figure 4.12). For concentrations. For each ATP hydrolyzed, three Na+ move out of a cell
each molecule of ATP hydrolyzed, this transporter moves three and two K+ move in.
Movement of Solutes and Water Across Cell Membranes 103
 Low Na+/High solute Intracellular fluid Low Na+/High solute Intracellular fluid H+/K+-ATPase is in the plasma
membranes of numerous cells, such
as the acid-secreting cells in the
Excess
– – – – – – negative – – –
–
stomach, where it pumps one H+ out
– – – – – – –
Transporter charge of the cell and moves one K+ in for
protein each molecule of ATP hydrolyzed.
Na+
The hydrogen ions enter the stomach
lumen where they have an important
Na+ function in the digestion of proteins.
Secondary Active Transport
In secondary active transport, the
movement of an ion down its electro-
chemical gradient is coupled to the
High Na+/Low solute High Na+/Low solute
Extracellular fluid transport of another molecule, often
Extracellular fluid
an organic nutrient like glucose or
Solute to be
cotransported
an amino acid. Thus, transport-
ers that mediate secondary active
Figure 4.13 Secondary active-transport model. In this example, the binding of a sodium ion to transport have two binding sites,
the transporter produces an allosteric increase in the affinity of the solute binding site at the extracellular one for an ion—typically but not
surface of the membrane. Binding of Na+ and solute causes a conformational change in the transporter that always Na+—and another for a sec-
exposes the binding sites to the intracellular fluid. Na+ diffuses down its electrochemical gradient into the
ond substance. An example of such
cell, which returns the solute binding site to a low-affinity state.
transport is shown in Figure 4.13.
In this example, the electrochemical
DIG DEEPER gradient for Na+ is directed into the
■ Is ATP hydrolyzed in the process of transporting solutes with secondary active transport? cell because of the higher concentra-
tion of Na+ in the extracellular fluid
Answer found in Appendix A.
and the excess negative charges
inside the cell. The other solute to
such plays a small role in the establishment of a cell’s membrane be transported, however, must move against its concentration gradi-
potential (see Figure 4.6). ent, uphill into the cell. High-affinity binding sites for Na+ exist on
+ +
In addition to the Na /K -ATPase transporter, the major pri- the extracellular surface of the transporter. Binding of Na+ increases
mary active-transport proteins found in most cells are: the affinity of the binding site for the transported solute. The trans-
porter then undergoes a conformational change, which exposes both
■■ Ca2+-ATPase
binding sites to the intracellular side of the membrane. When the
■■ H+-ATPase
transporter changes conformation, its affinity for Na+ decreases, and
■■ H+/K+-ATPase
Na+ moves into the intracellular fluid by simple diffusion down its
Together, the activities of these and other active-transport systems electrochemical gradient. At the same time, the affinity of the solute
account for a significant share of the total energy usage of the human binding site decreases, which releases the solute into the intracel-
body. Ca2+-ATPase is found in the plasma membrane and several lular fluid. Once the transporter releases both molecules, the protein
organelle membranes, including the membranes of the endoplasmic assumes its original conformation. The Na+ is then actively trans-
2+
reticulum. In the plasma membrane, the direction of active Ca ported back out of the cell by primary active transport, so that the
transport is from cytosol to extracellular fluid. In organelle mem- electrochemical gradient for Na+ is maintained. The secondarily
branes, it is from cytosol into the organelle lumen. Thus, active trans- transported solute remains in the cell.
port of Ca2+ out of the cytosol, via Ca2+-ATPase, is one reason that The most important distinction, therefore, between primary
the cytosol of most cells has a very low Ca2+ concentration, about and secondary active transport is that secondary active transport
10−7 mol/L, compared with an extracellular Ca2+ concentration of uses the stored energy of an electrochemical gradient to move
10−3 mol/L, 10,000 times greater. These transport mechanisms help both an ion and a second solute across a plasma membrane. The
ensure intracellular Ca2+ homeostasis, an important function because creation and maintenance of the electrochemical gradient, how-
of the many physiological activities in cells that are regulated by ever, depend on the action of primary active transporters.
changes in Ca2+ concentration (for example, release of cell secretions The creation of a Na+ concentration gradient across the
from storage vesicles into the extracellular fluid). plasma membrane by the primary active transport of Na+ is a means
+
H -ATPase is in the plasma membrane and several organ- of indirectly “storing” energy that can then be used to drive second-
elle membranes, including the inner mitochondrial and lysosomal ary active-transport pumps linked to Na+. Ultimately, however, the
+ +
membranes. In the plasma membrane, H -ATPase moves H pro- energy for secondary active transport is derived from metabolism in
duced by metabolism out of cells and in this way helps maintain the form of the ATP that is used by the Na+/K+-ATPase to create the
cellular pH. All enzymes in the body require a narrow range of pH Na+ concentration gradient. If the production of ATP were inhib-
for optimal activity; consequently, this active-transport process is ited, the primary active transport of Na+ would cease and the cell
vital for cell metabolism and survival. would no longer be able to maintain a Na+ concentration gradient
104 Chapter 4
 Extracellular fluid Composition of Extracellular
TABLE 4.1 and Intracellular Fluids
Plasma Intracellular fluid Extracellular Intracellular
membrane Concentration Concentration
(mM) (mM)*
High Na+ Low Na+ Na+ 145 15
Cotransport Low X High X +
K 5 150
Ca2+ 1 0.0001
2+
Mg 1.5 12

Extracellular fluid Cl− 100 7

−
HCO3 24 10
Intracellular fluid Pi 2 40
Amino acids 2 8
High Na+ Low Na+
Glucose 5.5 1
High X Low X
ATP 0 4
Countertransport
Protein 0.2 4
*The intracellular concentrations differ slightly from one tissue to another, depending on the expression
of plasma membrane ion channels and transporters. The intracellular concentrations shown in the table
are typical of most cells. For Ca2+, values represent free concentrations. Total calcium levels, including the
portion sequestered by proteins or in organelles, approach 2.5 mM (extracellular) and 1.5 mM (intracellular).

Figure 4.14 Cotransport and countertransport during

secondary active transport driven by Na+. Sodium ions always move Therefore, in secondary active transport, the movement of Na+ is
down their concentration gradient into a cell, and the transported always downhill, whereas the net movement of the actively trans-
solute always moves up its gradient. Both Na+ and the transported ported solute on the same transport protein is uphill, moving
solute X move in the same direction during cotransport, but in opposite from lower to higher concentration. The movement of the actively
directions during countertransport. transported solute can be either into the cell (in the same direc-
across the membrane. This, in turn, would lead to a failure of the tion as Na+), in which case it is known as cotransport, or out of
secondary active-transport systems that depend on the Na+ concen- the cell (opposite the direction of Na+ movement), which is called
tration gradient for their source of energy. countertransport (Figure 4.14). The terms symport and antiport
As noted earlier, the net movement of Na+ by a secondary are also used to refer to the processes of cotransport and counter-
active-transport protein is always from high extracellular con- transport, respectively.
centration into the cell, where the concentration of Na+ is lower. In summary, the distribution of substances between the
intracellular and extracellular fluid is often unequal (Table 4.1)
Na+
due to the presence in the plasma membrane of primary and
secondary active transporters, ion channels, and the membrane
potential. Table 4.2 provides a summary of the major charac-
H+ Ca2+ teristics of the different pathways by which substances move
through cell membranes, whereas Figure 4.15 illustrates the
K+
ADP ATP

Na+
ATP ADP
+
ADP ATP Figure 4.15 Movement of solutes across a typical plasma membrane
Na Amino
Primary acids involving membrane proteins. A specialized cell may contain additional
active transporters and channels not shown in this figure. Many of these membrane
transport
proteins can be modulated by various signals, leading to a controlled increase
Na+ or decrease in specific solute fluxes across the membrane. The stoichiometry of
K+
H+
Secondary
Ion
active
cotransporters is not shown.
channels
transport

Ca2+ DIG DEEPER: General Principle of Physiology

HCO3− +
Cl−
Na ■ This figure summarizes several of the many types of transporters in the
Facilitated
diffusion
cells of the human body. List a few ways in which the variety of transport
mechanisms shown here relate to the general principle of physiology that
homeostasis is essential for health and survival.
Ca2+ Cl− Answer found in Appendix A.

Glucose
Movement of Solutes and Water Across Cell Membranes 105
 TABLE 4.2 Major Characteristics of Pathways by Which Substances Cross Membranes
Diffusion Mediated Transport
Through Lipid Through Protein Facilitated Primary Active Secondary Active
Bilayer Channel Diffusion Transport Transport

Direction of net flux High to low High to low High to low Low to high Low to high
concentration concentration concentration concentration concentration

Equilibrium or steady state C o = Ci C o = C i* C o = Ci C o ≠ Ci C o ≠ Ci

Use of integral membrane No Yes Yes Yes Yes

protein

Maximal flux at high No No Yes Yes Yes

concentration (saturation)

Chemical specificity No Yes Yes Yes Yes

Use of energy and source No No No Yes: ATP Yes: ion gradient

(often Na+)

Typical molecules using Nonpolar: Ions: Polar: glucose Ions: Polar: amino acids,
pathway O2, CO2, fatty Na+, K+, Ca2+ Na+, K+, Ca2+, H+ glucose, some ions
acids
*In the presence of a membrane potential, the intracellular and extracellular ion concentrations will not be equal at steady state.

variety of commonly encountered channels and transporters St udy and Review 4.2—c ontinued
associated with the movement of substances across a typical
plasma membrane. ∙∙ Secondary active transport: binding of an ion (often Na+)
Not included in Table 4.2 is the mechanism by which water to the transporter drives the secondary-transport process;
moves across membranes. The special case whereby this polar mol- may be cotransport (same direction, such as into a cell) or
ecule moves between body fluid compartments is covered next. countertransport (opposite directions)
Review Question: Why is mediated transport required for the
movement of molecules such as glucose into or out of a cell?
Stu d y a n d Revi ew 4.2 Why is active transport required to move an ion against its
concentration gradient? (Answer found in Appendix A.)
■ Mediated transport: the movement of molecules or ions across
a membrane by binding the transported solute to a transporter
protein in the membrane
∙∙ Binding sites on transporters (proteins that move a
substance across a membrane) exhibit chemical specificity,
4.3 Osmosis
affinity, and saturation. Water is a polar molecule and yet it moves through the plasma
∙∙ The rate of transport depends on the degree of transporter membranes of most cells very rapidly. This process is mediated by a
saturation, the number of transporters in the membrane, and family of membrane proteins known as aquaporins that form chan-
the inherent rate at which conformational changes occur in nels through which water can move. The type and number of these
the transporter. water channels differ in different membranes. Consequently, some
■ Facilitated diffusion: mediated-transport process that moves cells are more permeable to water than others. Furthermore, in
molecules from higher to lower concentrations across a membrane some cells, the number of aquaporin channels—and, therefore, the
∙∙ requires a protein transporter and continues until the two permeability of the membrane to water—can be altered in response
concentrations become equal to various signals. This is especially important in the epithelial
∙∙ does not require metabolic energy (i.e., is “passive”) cells that line certain ducts in the kidneys. As you will learn in
­Chapter 14, one of the major functions of the kidneys is to regulate
■ Active transport: mediated-transport process that moves
the amount of water that gets excreted in the urine; this helps keep
molecules against an electrochemical gradient across a
the total amount of water in the body fluid compartments homeo-
membrane by means of a transporter and ATP
static. The epithelial cells of the kidney ducts contain numerous
∙∙ Primary active transport: phosphorylation of the
aquaporins that can be increased or decreased in number depend-
transporter by ATP drives the transport process; example is
ing on the water balance of the body at any time. For example, in
the Na+/K+-ATPase pump
an individual who is dehydrated, the numbers of aquaporins in the
membranes of the kidney epithelial cells will increase; this will
106 Chapter 4
permit additional water to move from the urine that is being formed adding solute to water will “dilute” the water. The greater the solute
in the kidney ducts back into the blood. That is why the volume of concentration, the lower the water concentration.
urine decreases whenever an individual becomes dehydrated. The degree to which the water concentration is decreased by
The net movement of water across a membrane is called the addition of solute depends upon the number of particles (mol-
osmosis. Osmosis proceeds from a region of low solute concen- ecules or ions) of solute in solution (the solute concentration) and not
tration to one of higher solute concentration. Another way to upon the chemical nature of the solute. For example, 1 mol of glu-
view this is that water moves from a region of high water con- cose in 1 L of solution decreases the water concentration to the same
centration to one of lower water concentration. Like simple diffu- extent as does 1 mol of an amino acid, or 1 mol of urea, or 1 mol of
sion, this movement is primarily entropy driven. Also, like simple any other molecule that exists as a single particle in solution. On the
diffusion, osmosis tends to equalize solute concentrations in two other hand, a molecule that ionizes in solution decreases the water
compartments, and occurs without a requirement for ATP hydro- concentration in proportion to the number of ions formed. For exam-
lysis. However, simple diffusion and osmosis across membranes ple, many simple salts dissociate nearly completely in water. For
are not exactly the same thing. As we will see shortly, osmosis simplicity’s sake, we will assume the dissociation is 100% at body
can be opposed by a force, namely hydrostatic pressure; there temperature and at concentrations found in the blood. Therefore,
is no opposing force that slows or stops diffusion of solutes. These 1 mol of sodium chloride in solution gives rise to 1 mol of sodium
and other biophysical considerations notwithstanding, it is useful ions and 1 mol of chloride ions, producing 2 mol of solute particles.
to consider the movement of water by osmosis as largely similar This decreases the water concentration twice as much as 1 mol of
to simple diffusion. glucose. By the same reasoning, if a 1 M MgCl2 solution were to dis-
The addition of a solute to water decreases the concentration sociate completely, it would decrease the water concentration three
of water in the solution compared to the concentration of pure water. times as much as would a 1 M glucose solution.
For example, if a solute such as glucose is dissolved in water, the Because the water concentration in a solution depends upon
concentration of water in the resulting solution is less than that of the number of solute particles, it is useful to have a concentra-
pure water. A given volume of a glucose solution contains fewer tion term that refers to the total concentration of solute particles
water molecules than an equal volume of pure water because each in a solution, regardless of their chemical composition. The total
glucose molecule occupies space formerly occupied by a water mole- solute concentration of a solution is known as its osmolarity. One
cule (Figure 4.16). In quantitative terms, a liter of pure water weighs osmol is equal to 1 mol of solute particles. Therefore, a 1 M solu-
about 1000 g, and the molecular weight of water is 18. Thus, the tion of glucose has a concentration of 1 Osm (1 osmol per liter),
concentration of water molecules in pure water is 1000/18 = 55.5 M. whereas a 1 M solution of NaCl contains 2 osmol of solute per
The decrease in water concentration in a solution is approximately liter of solution. A liter of solution containing 1 mol of glucose
equal to the concentration of added solute. In other words, one solute and 1 mol of NaCl has an osmolarity of 3 Osm. A solution with
molecule will displace one water molecule. The water concentration an osmolarity of 3 Osm may contain 1 mol of glucose and 1 mol
in a 1 M glucose solution is therefore approximately 54.5 M rather of NaCl, or 3 mol of glucose, or 1.5 mol of NaCl, or any other
than 55.5 M. Just as adding water to a solution will dilute the solute, combination of solutes as long as the total solute concentration is
equal to 3 Osm. (For reference, most physiological solutions, such
as blood, are usually in the milliosmolar range.)
Although osmolarity refers to the concentration of solute
particles, it also determines the water concentration in the solution
because the higher the osmolarity, the lower the water concentra-
tion. The concentration of water in any two solutions having the
same osmolarity is the same because the total number of solute
particles per unit volume is the same.
Let us now apply these principles governing water con-
centration to osmosis of water across membranes. Figure 4.17
Pure water
shows two 1 L compartments separated by a membrane perme-
Water molecule
(high water concentration) able to both solute and water. Initially, the concentration of sol-
Solute molecule ute is 2 Osm in compartment 1 and 4 Osm in compartment 2.
This difference in solute concentration means there is also a dif-
ference in water concentration across the membrane: 53.5 M in
compartment 1 and 51.5 M in compartment 2. Therefore, a net
diffusion of water from the higher concentration in compart-
ment 1 to the lower concentration in compartment 2 will take
place, and a net diffusion of solute in the opposite direction,
from 2 to 1. When diffusion equilibrium is reached, the two com-
partments will have identical solute and water concentrations,
3 Osm and 52.5 M, respectively. One mol of water will have dif-
Solution
(low water concentration) fused from compartment 1 to compartment 2, and 1 mol of solute
will have diffused from 2 to 1. Because 1 mol of solute has replaced
Figure 4.16 The addition of solute molecules to pure water lowers 1 mol of water in compartment 1, and vice versa in compartment 2,
the water concentration in the solution. no change in the volume occurs for either compartment.
Movement of Solutes and Water Across Cell Membranes 107
 Initial Initial

Water
Water

Solute

1 2 1 2
Solute 2 Osm 4 Osm Solute 2 Osm 4 Osm
Water 53.5 M 51.5 M Water 53.5 M 51.5 M
Volume 1L 1L Volume 1L 1L

Equilibrium Equilibrium

Solute 3 Osm 3 Osm Solute 3 Osm 3 Osm

Water 52.5 M 52.5 M Water 52.5 M 52.5 M
Volume 1L 1L Volume 0.67 L 1.33 L

Figure 4.17 Between two compartments of equal volume, the Figure 4.18 The movement of water across a membrane that
net diffusion of water and solute across a membrane permeable to both is permeable to water but not to solute leads to an equilibrium state
leads to diffusion equilibrium of both, with no change in the volume involving a change in the volumes of the two compartments. In this
of either compartment. (For clarity, not all water molecules are shown case, a net diffusion of water (0.33 L) occurs from compartment 1 to
here or in Figure 4.18.) 2. (We will assume that the membrane in this example stretches as the
volume of compartment 2 increases so that no significant change in
compartment pressure occurs.)
If the membrane is now replaced by one permeable to water
but impermeable to solute (Figure 4.18), the same concentrations
of water and solute will be reached at equilibrium as before, but a pressure to compartment 2. This leads to an important definition.
change in the volumes of the compartments will also occur. Water When a solution containing solutes is separated from pure water
will diffuse from 1 to 2, but there will be no solute diffusion in the by a semipermeable membrane (a membrane permeable to water
opposite direction because the membrane is impermeable to sol- but not to solutes), the pressure that must be applied to the solution
ute. Water will continue to diffuse into compartment 2, therefore, to prevent the net flow of water into it is known as the osmotic
until the water concentrations on the two sides become equal. The pressure of the solution. The greater the osmolarity of a solution,
solute concentration in compartment 2 decreases as it is diluted the greater the osmotic pressure. It is important to recognize that
by the incoming water, and the solute in compartment 1 becomes osmotic pressure does not push water molecules into a solution.
more concentrated as water moves out. When the water reaches Rather, it represents the amount of pressure that would have to be
diffusion equilibrium, the osmolarities of the compartments will applied to a solution to prevent the net flow of water into the solu-
be equal; therefore, the solute concentrations must also be equal. tion by osmosis. Like osmolarity, the osmotic pressure associated
To reach this state of equilibrium, enough water must pass from with a solution is a measure of the solution’s water concentration—
compartment 1 to 2 to increase the volume of compartment 2 by the lower the water concentration, the higher the osmotic pressure.
one-third and decrease the volume of compartment 1 by an equal
amount. Note that it is the presence of a membrane impermeable Extracellular Osmolarity and Cell Volume
to solute that leads to the volume changes associated with osmosis. We can now apply the principles learned about osmosis to cells,
The two compartments in our example were treated as if they which meet all the criteria necessary to produce an osmotic flow
were infinitely expandable, so the net transfer of water did not cre- of water across a membrane. Both the intracellular and extracellular
ate a pressure difference across the membrane. In contrast, if the fluids contain water, and cells are encased by a membrane that is very
walls of compartment 2 in Figure 4.18 had only a limited capacity to permeable to water but impermeable to many substances. Substances
expand, as occurs across plasma membranes, the movement of water that cannot cross the plasma membrane are called nonpenetrating
into compartment 2 would increase the pressure in compartment 2, solutes—that is, they do not penetrate through the lipid bilayer.
which would oppose further net water entry. Thus, the movement Most of the extracellular solute particles are sodium and
of water into compartment 2 can be prevented by the application of chloride ions, which can diffuse into the cell through ion channels
108 Chapter 4
in the plasma membrane or enter the cell during secondary active Such solutions are said to be isotonic (Figure 4.19), meaning
transport. As we have seen, however, the plasma membrane con- any solution that does not cause a change in cell size. Isotonic
tains Na+/K+-ATPase pumps that actively move Na+ out of the cell. solutions have the same concentration of nonpenetrating solutes
Therefore, Na+ moves into cells and is pumped back out, behaving as normal extracellular fluid. By contrast, hypotonic solutions
as if it never entered in the first place. For this reason, extracellular have a nonpenetrating solute concentration lower than that found
Na+ behaves as a nonpenetrating solute. Any chloride ions that enter in cells; therefore, water moves by osmosis into the cells, caus-
cells are also removed as quickly as they enter, due to the electrical ing them to swell. Similarly, solutions containing greater than
repulsion generated by the membrane potential and the action of 300 mOsm of nonpenetrating solutes (hypertonic solutions)
various transporters. Like Na+, therefore, extracellular chloride ions cause cells to shrink as water diffuses out of the cell into the
behave as if they were nonpenetrating solutes. fluid with the lower water concentration.
Inside the cell, the major solute particles are K+ and a num- The concentration of nonpenetrating solutes in a solu-
ber of organic solutes. Most of the latter are large polar molecules tion, not the total osmolarity, determines its tonicity—
unable to diffuse through the plasma membrane. Although K+ can isotonic, hypotonic, or hypertonic. By contrast, solutes that readily
diffuse out of a cell through K+ channels, it is actively transported diffuse through lipid bilayers (penetrating solutes) do not contrib-
back by the Na+/K+-ATPase pump. The net effect, as with extra- ute to the tonicity of a solution. This is so because the concentra-
cellular Na+ and Cl−, is that K+ behaves as if it were a nonpenetrat- tions of penetrating solutes rapidly equilibrate across the membrane.
ing solute, but in this case one confined to the intracellular fluid. Another set of terms—isoosmotic, hypoosmotic, and
Therefore, Na+ and Cl− outside the cell and K+ and organic solutes hyperosmotic—denotes the osmolarity of a solution relative to
inside the cell behave as nonpenetrating solutes on the two sides of that of normal extracellular fluid without regard to whether the
the plasma membrane. solute is penetrating or nonpenetrating. The two sets of terms are
The osmolarity of the extracellular fluid is normally in the therefore not synonymous. For example, a 1 L solution containing
range of 285–300 mOsm (we will round off to a value of 300 for 150 mOsm each of nonpenetrating Na+ and Cl− and 100 mOsm of
the rest of this text unless otherwise noted). Because water can dif- urea, which can rapidly cross plasma membranes, would have a
fuse across plasma membranes, water in the intracellular and extra- total osmolarity of 400 mOsm and would be hyperosmotic relative
cellular fluids will come to diffusion equilibrium. At equilibrium, to a typical cell. It would, however, also be an isotonic solution,
therefore, the osmolarities of the intracellular and extracellular fluids producing no change in the equilibrium volume of cells immersed
are the same—approximately 300 mOsm. Changes in extracellular in it. Initially, cells placed in this solution would shrink as water
osmolarity can cause cells, such as the red blood cells shown in the moved into the extracellular fluid. However, urea, as a penetrating
chapter-opening photo, to shrink or swell as water molecules move solute, would quickly diffuse into the cells and reach the same con-
across the plasma membrane. centration as the urea in the extracellular solution; consequently,
If cells with an intracellular osmolarity of 300 mOsm are both the intracellular and extracellular solutions would soon reach
placed in a solution of nonpenetrating solutes having an osmo- the same osmolarity. Therefore, at equilibrium, there would
larity of 300 mOsm, they will neither swell nor shrink because be no difference in the water concentration across the membrane
the water concentrations in the intracellular and extracellu- and thus no change in final cell volume; this would be the case
lar fluids are the same, and the solutes cannot leave or enter. even though the extracellular fluid would remain hyperosmotic
relative to the normal value of 300 mOsm. Table 4.3 provides a
Intracellular fluid 300 mOsm comparison of the various terms used to describe the osmolarity
nonpenetrating solutes and tonicity of solutions.
Normal cell volume

Figure 4.19 Changes in cell volume

produced by hypertonic, isotonic, and hypotonic
solutions.

DIG DEEPER
■ Blood volume must be restored in a person
who has lost large amounts of blood due to
serious injury. This is often accomplished
by infusing isotonic NaCl solution into
the blood. Why is this more effective
400 mOsm 300 mOsm 200 mOsm than infusing an isoosmotic solution of a
nonpenetrating solutes nonpenetrating solutes nonpenetrating solutes penetrating solute, such as urea?
Hypertonic solution Isotonic solution Hypotonic solution Answer found in Appendix A.
Cell shrinks No change in cell volume Cell swells

Movement of Solutes and Water Across Cell Membranes 109

 Terms Referring to the Osmolarity St udy and Review 4.3—c ontinued
TABLE 4.3 and Tonicity of Solutions*
∙∙ K+ and various organic solutes are the major nonpenetrating
Isotonic A solution that does not cause a change in solutes in the intracellular fluid.
cell volume; one that contains 300 mOsmol/L
of nonpenetrating solutes, regardless of the ■ Tonicity: a measure of the ability of a solution to add or remove
concentration of membrane-penetrating water from cells due to osmosis
solutes present ∙∙ Isotonic solution: does not cause a change in cell volume
∙∙ Hypotonic solution: causes cells to swell in volume due to
Hypertonic A solution that causes cells to shrink; one having a lower concentration of nonpenetrating solutes than
that contains greater than 300 mOsmol/L the cell interior
of nonpenetrating solutes, regardless of the
∙∙ Hypertonic solution: causes cells to shrink in volume due to
concentration of membrane-penetrating
having a higher concentration of nonpenetrating solutes than
solutes present
the cell interior
Hypotonic A solution that causes cells to swell; one Review Question: What is meant by “penetrating” and
that contains less than 300 mOsmol/L of “nonpenetrating” solutes? Does the latter mean that a solute
nonpenetrating solutes, regardless of the cannot cross a membrane by any means? (Answer found in
concentration of membrane-penetrating Appendix A.)
solutes present

Isoosmotic A solution containing 300 mOsmol/L of

solute, regardless of its composition of
membrane-penetrating and nonpenetrating
solutes
4.4 Endocytosis and Exocytosis
Hyperosmotic A solution containing greater than In addition to diffusion and mediated transport, there is
300 mOsmol/L of solutes, regardless of its another pathway by which substances can enter or leave cells,
composition of membrane-penetrating and
one that does not require the molecules to pass through the
nonpenetrating solutes
structural matrix of the plasma membrane. When sections of
Hypoosmotic A solution containing less than cells are observed under an electron microscope, regions of the
300 mOsmol/L of solutes, regardless of its plasma membrane can often be seen to have folded into the
composition of membrane-penetrating and cell, forming small pockets that pinch off to produce intracel-
nonpenetrating solutes lular, membrane-bound vesicles that enclose a small volume of
*These terms are defined using an intracellular osmolarity of 300 mOsm as a reference, which is within the
extracellular fluid. This process is known as endocytosis (Fig-
range for human cells but not an absolute fixed number. ure 4.20). The reverse process, exocytosis, occurs when mem-
brane-bound vesicles in the cytoplasm fuse with the plasma
membrane and release their contents to the outside of the cell
(see Figure 4.20).
Stu d y a n d Revi ew 4.3
■ Osmolarity: total solute concentration in a solution; 1 osmol =
1 mol of solute particles; the higher the osmolarity of a solution,
the lower the water concentration
■ Osmosis: diffusion of water across a membrane through Intracellular
aquaporins (water channels) from a region of higher water Nucleus fluid
concentration to a region of lower water concentration
■ Semipermeable membrane: a membrane permeable to water
but not to solutes Endocytosis Exocytosis
■ Osmosis across a semipermeable membrane leads to an
increase in the volume of the compartment on the side that
initially had the higher osmolarity, and a decrease in the
volume on the side that initially had the lower osmolarity.
■ Intracellular and extracellular fluid compartments typically
Plasma
have the same osmolarity, about 300 mOsm/L. membrane
∙∙ Na+ and Cl− are the major nonpenetrating solutes (that Extracellular fluid
Solute
is, cannot freely diffuse through the lipid bilayer) in the molecule
extracellular fluid.
Figure 4.20 Endocytosis and exocytosis.
110 Chapter 4
 Golgi
Nonspecific Nucleus apparatus
uptake of Ligand
solutes Receptor Nucleus
and H2O

Solutes Vesicle
Clathrin proteins
forming a
clathrin- Unbound
Plasma coated pit ligand
membrane
Vesicle

Lysosome
Extracellular fluid
Clathrin proteins
(a) Pinocytosis (fluid endocytosis) being released
from vesicle

Bacterium Nucleus Receptor

Lysosome Endosome Receptor recycled
Cytosol to membrane
Vesicle
formation

Pseudopodia (c) Receptor-mediated endocytosis

Phagosome

Extracellular fluid

(b) Phagocytosis

Figure 4.21 Pinocytosis, phagocytosis, and receptor-mediated endocytosis. (a) In pinocytosis, solutes and water are nonspecifically brought
into the cell from the extracellular fluid via endocytotic vesicles. (b) In phagocytosis, specialized cells form extensions of the plasma membrane called
pseudopodia, which engulf bacteria or other large objects such as cell debris. The vesicles that form fuse with lysosomes, which contain enzymes and
other molecules that destroy the vesicle contents. (c) In receptor-mediated endocytosis, a cell recognizes a specific extracellular ligand that binds to a
plasma membrane receptor. The binding triggers endocytosis. In the example shown here, the ligand-receptor complexes are internalized via clathrin-
coated vesicles, which merge with endosomes (for simplicity, adaptor proteins are not shown). Ligands may be routed to the Golgi apparatus for further
processing, or to lysosomes. The receptors are typically recycled to the plasma membrane.

Endocytosis and the contents of the phagosomes are then destroyed by lyso-
somal enzymes and other molecules. Whereas most cells undergo
Three common types of endocytosis may occur in a cell. These
pinocytosis, only a few special types of cells, such as those of the
are pinocytosis (“cell drinking”), phagocytosis (“cell eating”), and
immune system (Chapter 18), carry out phagocytosis.
receptor-mediated endocytosis (Figure 4.21).

Pinocytosis Receptor-Mediated Endocytosis

In pinocytosis, also known as fluid endocytosis, an endocytotic In contrast to pinocytosis and phagocytosis, most cells have the
vesicle encloses a small volume of extracellular fluid. This process capacity to specifically take up molecules that are important for
is nonspecific because the vesicle simply engulfs the water in the cellular function or structure. In receptor-mediated endocytosis,
extracellular fluid along with whatever solutes are present. These certain molecules in the extracellular fluid bind to specific pro-
solutes may include ions, nutrients, or any other small extracel- teins on the outer surface of the plasma membrane. These pro-
lular molecule. Large macromolecules, other cells, and cell debris teins are called receptors, and each one recognizes one ligand
do not normally enter a cell via this process. with high affinity (see Section 3.8 for a discussion of ligand–pro-
tein interactions). In one form of receptor-mediated endocytosis,
Phagocytosis the receptor undergoes a conformational change when it binds a
In phagocytosis, cells engulf bacteria or large particles such ligand. Through a series of steps, a cytosolic protein called clath-
as cell debris from damaged tissues. In this form of endocy- rin is recruited to the plasma membrane. A class of proteins called
tosis, extensions of the plasma membrane called pseudopodia adaptor proteins links the ligand-receptor complex to clathrin. The
fold around the surface of the particle, engulfing it entirely. The entire complex then forms a cagelike structure that leads to the
pseudopodia, with their engulfed contents, then fuse into large aggregation of ligand-bound receptors into a localized region of
vesicles called phagosomes that are internalized into the cell. membrane, forming a depression, or clathrin-coated pit, which
Phagosomes migrate to and fuse with lysosomes in the cytoplasm, then invaginates and pinches off to form a clathrin-coated vesicle.
Movement of Solutes and Water Across Cell Membranes 111
 By localizing ligand-receptor complexes to discrete patches formed proteins into the lumen of the endoplasmic reticulum and
of plasma membrane prior to endocytosis, cells may obtain con- the protein’s processing through the Golgi apparatus. From the
centrated amounts of ligands without having to engulf large Golgi apparatus, the proteins to be secreted travel to the plasma
amounts of extracellular fluid from many different sites along the membrane in vesicles from which they can be released into the
membrane. Receptor-mediated endocytosis, therefore, leads to extracellular fluid by exocytosis. In some cases, substances enter
a selective concentration in the endocytotic vesicle of a specific vesicles via mediated transporters in the vesicle membrane.
ligand bound to one type of receptor. The secretion of substances by exocytosis is triggered in
Once an endocytotic vesicle pinches off from the plasma most cells by stimuli that lead to an increase in cytosolic Ca2+
membrane in receptor-mediated endocytosis, the clathrin coat is concentration in the cell. As will be described in Chapters 5 and 6,
removed and clathrin proteins are recycled back to the membrane. these stimuli open Ca2+ channels in the plasma membrane and/or
The vesicles then have several possible fates, depending upon the the membranes of intracellular organelles. The resulting increase
cell type and the ligand that was engulfed. Some vesicles fuse with in cytosolic Ca2+ concentration activates proteins required for
the membrane of an intracellular organelle, adding the contents of the vesicle membrane to fuse with the plasma membrane and
the vesicle to the lumen of that organelle. Other endocytotic vesicles release the vesicle contents into the extracellular fluid. Mate-
pass through the cytoplasm and fuse with the plasma membrane on rial stored in secretory vesicles is available for rapid secretion
the opposite side of the cell, releasing their contents to the extracel- in response to a stimulus, without delays that might occur if the
lular space. This provides a pathway for the transfer of large mol- material had to be synthesized after the stimulus arrived.
ecules, such as proteins, across the layers of cells that separate two Exocytosis is the mechanism by which most neurons com-
fluid compartments in the body (for example, the blood and inter- municate with each other through the release of neurotransmitters
stitial fluid). A similar process allows small amounts of macromol- stored in secretory vesicles that merge with the plasma mem-
ecules to move across the intestinal epithelium. brane. It is also a major way in which many types of hormones are
Most endocytotic vesicles fuse with a series of intracellular released from endocrine cells into the extracellular fluid.
vesicles and tubular elements known as endosomes (Chapter 3), Cells that actively undergo exocytosis recover bits of mem-
which lie between the plasma membrane and the Golgi appara- brane via a process called compensatory endocytosis. This process,
tus. Like the Golgi apparatus, the endosomes perform a sorting the mechanisms of which are still uncertain but that may involve
function, distributing the contents of the vesicle and its membrane both clathrin- and non-clathrin-mediated events, restores membrane
to various locations. Some of the contents of endocytotic vesicles material to the cytoplasm that can be made available for the forma-
are passed from the endosomes to the Golgi apparatus, where the tion of new secretory vesicles. It also helps prevent the plasma mem-
ligands are modified and processed. Other vesicles fuse with lyso- brane’s unchecked expansion.
somes, organelles that contain digestive enzymes that break down
large molecules such as proteins, polysaccharides, and nucleic
acids. The fusion of endosomal vesicles with the lysosomal
membrane exposes the contents of the vesicle to these digestive St udy and Review 4.4
enzymes. Finally, in many cases, the receptors that were internal-
ized with the vesicle get recycled back to the plasma membrane. ■ Endocytosis: process in which regions of the plasma
Each episode of endocytosis removes a small portion of the membrane invaginate and pinch off to form vesicles that
membrane from the cell surface. In cells that have a great deal of enclose a small volume of extracellular material
endocytotic activity, more than 100% of the plasma membrane may ∙∙ Pinocytosis (fluid endocytosis): cells engulf extracellular
be internalized in an hour, yet the membrane surface area remains fluid and its solutes
constant. This is because the membrane is replaced at about the ∙∙ Phagocytosis: cells engulf bacteria or other large particles
same rate by vesicle membrane that fuses with the plasma mem- ∙∙ Receptor-mediated endocytosis: clathrin-coated pits are
brane during exocytosis. Some of the plasma membrane proteins formed by pinching off regions of membrane that contain
taken into the cell during endocytosis are stored in the membranes receptor-ligand complexes
of endosomes and, upon receiving the appropriate signal, can be ■ Most endocytotic vesicles fuse with endosomes, which in
returned to fuse with the plasma membrane during exocytosis. turn transfer the vesicle contents to lysosomes for digestion by
lysosomal enzymes.

Exocytosis ■ Exocytosis: process in which intracellular vesicles fuse with

the plasma membrane
Exocytosis performs two functions for cells:
∙∙ One function is to add components to the plasma membrane.
■■ It provides a way to replace portions of the plasma ∙∙ Another function is to release cellular products into the
membrane that endocytosis has removed and, in the extracellular fluid.
process, a way to add new membrane components
Review Question: What type of molecules in a cell typically
as well. require exocytosis in order to be secreted? What key ion is
■■ It provides a route by which membrane-impermeable required in the cytosol for exocytosis to occur? What types of
molecules (such as protein hormones) that the cell molecules would not be expected to require exocytosis, but
synthesizes can be secreted into the extracellular fluid. instead might leave the cell in another way such as diffusion?
(Answer found in Appendix A.)
How does the cell package substances that are to be secreted
by exocytosis into vesicles? Chapter 3 described the entry of newly
112 Chapter 4
4.5 Epithelial Transport substances between the kidney tubules and the blood during
urine formation, and the secretion of ions and water by glands
As described in Chapter 1, epithelial cells line hollow organs or such as sweat glands.
tubes and regulate the absorption or secretion of substances across Figure 4.23 and Figure 4.24 illustrate two examples of
these surfaces. One surface of an epithelial cell generally faces a active transport across an epithelium. Na+ is actively transported
hollow or fluid-filled tube or chamber, and the plasma membrane across most epithelia from lumen to blood side. In our exam-
on this side is referred to as the apical membrane (also known ple, the movement of Na+ from the lumen into the epithelial cell
as the luminal membrane) (refer back to Figures 1.2 and 3.9). The occurs by diffusion through Na+ channels in the apical mem-
plasma membrane on the opposite surface rests upon a basement brane (see Figure 4.23). Na+ diffuses into the cell because the
membrane and is usually adjacent to a network of blood vessels; intracellular concentration of Na+ is kept low by the active trans-
it is referred to as the basolateral membrane (also known as the port of Na+ back out of the cell across the basolateral membrane
serosal membrane). on the opposite side, where all of the Na+/K+-ATPase pumps are
The two pathways by which a substance can cross a layer located. In other words, Na+ moves downhill into the cell and
of epithelial cells are (1) the paracellular pathway, in which dif- then uphill out of it. The net result is that Na+ can be moved
fusion occurs between the adjacent cells of the epithelium; and via the transcellular pathway from lower to higher concentration
(2) the transcellular pathway, in which a substance moves into across the epithelium.
an epithelial cell across either the apical or basolateral mem- Figure 4.24 illustrates the active absorption of organic
brane, diffuses through the cytosol, and exits across the oppo- molecules across an epithelium, again by a transcellular path-
site membrane (Figure 4.22). Diffusion through the paracellular way. In this case, the entry of an organic molecule X across the
pathway is limited by the presence of tight junctions between apical plasma membrane occurs via a secondary active trans-
adjacent cells, because these junctions form a seal around the porter linked to the downhill movement of Na+ into the cell. In
apical end of the epithelial cells (Chapter 3). Although small
ions and water can diffuse to some degree through tight junc-
tions, the amount of paracellular diffusion is limited by the tight-
ness of the junctional seal and the relatively small area available Lumen side Epithelial cell Blood side
for diffusion. ATP
3 Na+
Na+ Na+
During transcellular transport, the movement of mol-
2 K+
ecules through the plasma membranes of epithelial cells occurs
via the pathways (diffusion and mediated transport) already Sodium Na+/K+-
ADP
described for movement across membranes. However, the channel ATPase
transport and permeability characteristics of the apical and pump
basolateral membranes are not the same. These two mem-
branes often contain different ion channels and different trans- Blood
vessel
porters for mediated transport. As a result of these differences,
substances can undergo a net movement from a low concen-
tration on one side of an epithelium to a higher concentration Extracellular
on the other side. Examples include the absorption of material
Sodium concentration

concentration
from the gastrointestinal tract into the blood, the movement of Lumen Intracellular
concentration concentration

Lumen side Epithelial cell Blood side Active transport

Tight junction Diffusion
Basolateral
membranes

Figure 4.23 Active transport of Na+ across an epithelial cell. The

transepithelial transport of Na+ always involves primary active transport
Transcellular
out of the cell across one of the plasma membranes, typically via an
pathway Na+/K+-ATPase pump as shown here. The movement of Na+ into the cell
across the plasma membrane on the opposite side is always downhill.
Sometimes, as in this example, it is by diffusion through Na+ channels,
Apical membrane whereas in other epithelia this downhill movement occurs through a
secondary active transporter. Shown below the cell is the concentration
Paracellular profile of the transported solute across the epithelium.
pathway
Blood DIG DEEPER
vessel
■ What would happen in this situation if the cell’s ATP supply
Figure 4.22 The two major routes by which water and solutes decreased significantly?
move across an epithelium, shown here as moving from the lumen of a Answer found in Appendix A.
tube or hollow chamber into the blood.
Movement of Solutes and Water Across Cell Membranes 113
 Lumen side Epithelial cell Blood side Lumen side Epithelial cell Blood side
Tight junction
Facilitated
diffusion Basolateral
H2O H2O membranes

Na+ Na+
X X

3 Na+
ATP ATP

3 Na+ Na+ Na+

X X

2 K+ Apical 2 K+
Secondary
active Blood membrane ADP
transport ADP
vessel
H2O H2O H2O
H2O

H2O Blood
H2O
Extracellular vessel
concentration Tight junction
X concentration

Lumen Intracellular
concentration concentration
Figure 4.25 Net movements of water across an epithelium are
Active Facilitated dependent on net solute movements. The active transport of Na+ across
transport diffusion the cells and into the surrounding interstitial spaces produces an
elevated osmolarity in this region and a decreased osmolarity in the
lumen. This leads to the osmotic flow of water across the epithelium
in the same direction as the net solute movement. The water diffuses
Figure 4.24 The transepithelial transport of most organic solutes through aquaporins in the membrane (transcellular pathway) and across
(X) involves their movement into a cell through a secondary active the tight junctions between the epithelial cells (paracellular pathway).
transport driven by the downhill flow of Na+. The organic substance
then moves out of the cell at the blood side down a concentration
gradient by means of facilitated diffusion. Shown below the cell DIG DEEPER: General Principle of Physiology
is the concentration profile of the transported solute across the ■ A general principle of physiology is that structure is a determinant
epithelium. of—and has coevolved with—function. What features of epithelial
cells shown in this figure lend support to that principle?
Answer found in Appendix A.

the process, X moves from a lower concentration in the luminal

fluid to a higher concentration in the cell. The substance exits
across the basolateral membrane by facilitated diffusion, which
moves the material from its higher concentration in the cell to a
lower concentration in the extracellular fluid on the blood side. St udy and Review 4.5
The concentration of the substance may be considerably higher
■ Paracellular pathway: movement of molecules across an
on the blood side than in the lumen because the blood-side con-
epithelium through the spaces and tight junctions between
centration can approach equilibrium with the high intracellular
epithelial cells
concentration created by the apical membrane entry step.
Although water is not actively transported across cell ■ Transcellular pathway: movement of molecules across an
membranes, net movement of water across an epithelium can epithelium through the cell
occur by osmosis as a result of the active transport of solutes, ∙∙ Molecules first move into the cell across the apical (lumen-
notably Na+, across the epithelium. The active transport of Na+, facing side) membrane, through the cytoplasm, and then
as previously described, results in a decrease in the Na+ con- out across the basolateral (basement membrane side)
centration on one side of an epithelial layer (the luminal side membrane, or the reverse.
in our example) and an increase on the other. These changes in ■ Properties of apical and basolateral plasma membranes differ,
solute concentration are accompanied by changes in the water allowing for active transport of a substance in a given direction
concentration on the two sides because a change in solute con- across an epithelium.
centration, as we have seen, produces a change in water concen- ■ Active transport of Na+ across an epithelium increases the
tration. The water concentration difference will cause water to osmolarity on one side of the cell and decreases it on the other,
move by osmosis from the low-Na+ side to the high-Na+ side of causing water to move by osmosis in the same direction as the
the epithelium (Figure 4.25). Therefore, net movement of solute transported Na+.
across an epithelium is accompanied by a flow of water in the Review Question: What properties of epithelial cells make
same direction. As you will learn in Chapter 14, this is a major them an ideal barrier to separate two regions from each other?
way in which epithelial cells of the kidney absorb water from the (Answer found in Appendix A.)
urine back into the blood. It is also the major way in which water
is absorbed from the intestines into the blood (Chapter 15).
114 Chapter 4
CHAPTER 4 Clinical Case Study: A Novice Marathoner Collapses After a Race
A 22-year-old, 46.4 kg (102-pound)
woman who had occasionally competed
in short-distance races decided to com-
pete in her first marathon. She was in
good health but was completely inex-
perienced in long-distance runs. Dur-
ing the hour before the race, she drank
1.2 liters of water (about two 20-ounce
Comstock Images/Getty Images bottles) in anticipation of the water loss
she expected to occur due to perspira-
tion over the next few hours. The race
took place on an unseasonably cool day in April. As she ran, she was
careful to drink a cup of water (about 200 mL) at each water station, Normal cell Swollen cell
roughly each mile along the course. Being a newcomer to competing
Figure 4.26 A normal red blood cell (left) and one that has
in marathons, she had already been running for 3 hours at the 20-mile swelled due to osmotic movement of water into the cell. Compare the
mark and was beginning to feel extremely fatigued. Soon after, her leg appearance of this cell with the ones in the chapter-opening image,
muscles began cramping. Thinking she was losing too much fluid, she which have lost water due to osmosis. David M. Phillips/Science Source
stopped for a moment at a water station and drank several cups of water,
then continued on. After another 2 miles, she consumed a full 0.6 L bot-
tle of water; a mile later, she began to feel confused and disoriented and
developed a headache. At that point, she became panicked that she
In addition, however, recall from Figure 4.19 what hap-
would not finish the race; even though she did not feel thirsty, she fin-
pens to cells when the concentrations of nonpenetrating sol-
ished yet another bottle of water. Twenty minutes later, she collapsed,
utes across the cell membrane are changed. As our subject’s
lost consciousness, and was taken by ambulance to a local hospital. She
extracellular fluid became more dilute than her intracellular
was diagnosed with exercise-associated hyponatremia (EAH), a condi-
fluid, water moved by osmosis into her cells. Many types of cells,
tion in which the concentration of Na+ in the blood decreases to danger-
including those of the brain, are seriously damaged when they
ously low levels (in her case, to 115 mM; see Table 4.1 for comparison).
swell due to water influx (Figure 4.26). It is even worse in the
Reflect and Review #1 brain than elsewhere because there is no room for the brain to
■■ How much total water did the woman consume before and expand within the skull. As brain cells swell, the fluid pressure in
during the race? How does that volume compare to an the brain increases, compressing blood vessels and restricting
estimate of the total extracellular fluid volume in a 102-pound blood flow. When blood flow is reduced, oxygen and nutrient
woman? (See Figure 1.3 for help.) levels decrease and metabolic waste products build up, further
It was clear to her physicians what caused the EAH. When we contributing to brain cell malfunction. Thus, the combination of
exercise, perspiration helps cool us down. Sweat is a dilute solution water influx, increased pressure, and changes in the electro-
of several ions, particularly Na+ (the other major ones being Cl− and chemical gradient for Na+ all contributed to the mental distur-
K+). The result of excessive sweating is that the total amount of water bances and subsequent loss of consciousness in our subject.
and Na+ in the body becomes depleted. Our subject was exercising What do you think would be an appropriate way to treat
very hard and for a very long time but was not losing as much fluid as EAH? Remember, the person is not dehydrated. In fact, one of
she had anticipated because of the cool weather. She was wise to be the best predictors of EAH in subjects like ours is weight gain
aware of the potential for fluid loss, but she was not aware that drinking during a marathon; such individuals actually weigh more at the
pure water in such quantities could significantly dilute her body fluids. end of a race than at the beginning because of all the water they
drink! The treatment is an intravenous infusion of an isotonic
Reflect and Review #2
solution of NaCl to bring the total levels of Na+ in the body fluids
■■ What effect might a change in extracellular osmolarity have on back toward normal. At the same time, however, the extracel-
the movement of water across cell membranes (you can assume lular fluid volume is reduced with a diuretic (a medication that
that plasma and interstitial fluid osmolarities are the same)? increases the amount of water excreted in the urine). In addition,
As the concentration of Na+ in her extracellular fluid decreased, patients may also receive medications to prevent or stop sei-
the electrochemical gradient for Na+ across her cells—including her zures. As you will learn in Chapters 6 and 8, a seizure is uncon-
muscle and brain cells—also decreased as a consequence. As you trolled, unregulated electrical activity of the neurons in the brain;
will learn in detail in Chapters 6 and 9, the electrochemical gradi- one potential cause of a seizure is a large imbalance in extra-
ent for Na+ is part of what regulates the function of skeletal muscle cellular ion concentrations in the brain. In our subject, gradual
and brain cells. As a result of disrupting this gradient, our subject’s restoration of a normal Na+ concentration was sufficient to save
muscles and neurons began to malfunction, accounting in part for her life, but careful monitoring of her progress over the course of
the cramps and mental confusion. a 24-hour hospital stay was required.

See Chapter 19 for complete, integrative case studies.

 hypotonic osmolarity
K EY A N D CL INICA L T ER M S isoosmotic osmosis
isotonic osmotic pressure
4.1 Diffusion
nonpenetrating solutes penetrating solutes
channel gating ligand-gated ion channels osmol semipermeable membrane
diffusion equilibrium mechanically gated ion channels
electrochemical gradient membrane potential 4.4 Endocytosis and Exocytosis
Fick’s first law of diffusion net flux
clathrin phagocytosis
flux simple diffusion
clathrin-coated pit phagosomes
ion channels voltage-gated ion channels
endocytosis pinocytosis
exocytosis receptor-mediated endocytosis
4.2 Mediated-Transport Systems
fluid endocytosis receptors
active transport Na+/K+-ATPase pump
cotransport primary active transport 4.5 Epithelial Transport
countertransport secondary active transport
apical membrane paracellular pathway
facilitated diffusion transporters
basolateral membrane transcellular pathway
mediated transport

Clinical Case Study

4.3 Osmosis
exercise-associated
aquaporins hypertonic
hyponatremia (EAH)
hyperosmotic hypoosmotic

CHAPTER 4 TEST QU E ST ION S Recall and Comprehend Answers appear in Appendix A.

These questions test your recall of important details covered in this chapter. They also help prepare you for the type of questions
encountered in standardized exams. Many additional questions of this type are available on Connect and LearnSmart.

1. Which properties are characteristic of ion channels? d. They depend upon the activity of Na+/K+-ATPase pumps for much of
a. They are usually lipids. their transport functions.
b. They exist on one side of the plasma membrane, usually the e. Both b and d are correct.
intracellular side. 5. Which is incorrect?
c. They can open and close depending on the presence of any of three a. Diffusion of a solute through a membrane is considerably quicker than
types of “gates.” diffusion of the same solute through a water layer of equal thickness.
d. They permit movement of ions against electrochemical gradients. b. A single ion, such as K+, can diffuse through more than one type of
e. They mediate facilitated diffusion. channel.
2. Which of the following does not directly or indirectly require an energy c. Lipid-soluble solutes diffuse more readily through the phospholipid
source? bilayer of a plasma membrane than do water-soluble ones.
a. primary active transport d. The rate of facilitated diffusion of a solute is limited by the number of
b. operation of the Na+/K+-ATPase pump transporters in the membrane at any given time.
c. the mechanism used by cells to produce a calcium ion gradient across e. A common example of cotransport is that of an ion and an organic molecule.
the plasma membrane 6. In considering diffusion of ions through an ion channel, which driving
d. facilitated transport of glucose across a plasma membrane force/forces must be considered?
e. secondary active transport a. the ion concentration gradient
3. If a small amount of urea were added to an isoosmotic saline solution b. the electrical gradient
containing cells, what would be the result? c. osmosis
a. The cells would shrink and remain that way. d. facilitated diffusion
b. The cells would first shrink but then be restored to normal volume after e. both a and b
a brief period of time.
7. The difference between the fluxes of a solute moving in two opposite
c. The cells would swell and remain that way.
directions is the    .
d. The cells would first swell but then be restored to normal volume after
a brief period of time. 8. In     , membrane-bound vesicles in the cytosol of a cell fuse with the
e. The urea would have no effect, even transiently. plasma membrane and release their contents to the extracellular fluid.
4. Which is/are true of epithelial cells? 9. The channels through which water moves across plasma membranes are
a. They can only move uncharged molecules across their surfaces. called    .
b. They may have segregated functions on apical (luminal) and basolateral 10.     is the name of the process by which glucose moves across a plasma
surfaces. membrane.
c. They cannot form tight junctions.

116 Chapter 4
 CHAPTER 4 T E ST QU E ST I ONS Apply, Analyze, and Evaluate Answers appear in Appendix A.

These questions, which are designed to be challenging, require you to integrate concepts covered in the chapter to draw your own
conclusions. See if you can first answer the questions without using the hints that are provided; then, if you are having difficulty, refer
back to the figures or sections indicated in the hints.

1. In two cases (A and B), the concentrations of solute X in two 1 L 5. Assume that a membrane separating two compartments is permeable to
compartments separated by a membrane through which X can diffuse are urea but not permeable to NaCl. If compartment 1 contains 200 mmol/L of
NaCl and 100 mmol/L of urea, and compartment 2 contains 100 mmol/L
Concentration of X (mM) of NaCl and 300 mmol/L of urea, which compartment will have increased
Case Compartment 1 Compartment 2 in volume when osmotic equilibrium is reached? Hint: See Figure 4.19 and
Table 4.3.
A 3 5
6. What will happen to cell volume if a cell is placed in each of the following
B 32 30 solutions? Hint: See Figure 4.19 and Table 4.3.
a. In what direction will the net flux of X take place in case A and in case B? Concentration of X (mM)
b. When diffusion equilibrium is reached, what will the concentration of
NaCl Urea
solute in each compartment be in case A and in case B?
Solution (Nonpenetrating) (Penetrating)
c. Will A reach diffusion equilibrium faster, slower, or at the same rate as
B? Hint: See Figures 4.1–4.3. A 150 100
2. If a transporter that mediates active transport of a substance has a lower B 100 150
affinity for the transported substance on the extracellular surface of the
C 200 100
plasma membrane than on the intracellular surface, in what direction
will there be a net transport of the substance across the membrane? Hint: D 100 50
See Figure 4.11 and assume that the rate of transporter conformational 7. Characterize each of the solutions in question 6 as isotonic, hypotonic,
change is the same in both directions. hypertonic, isoosmotic, hypoosmotic, or hyperosmotic. Hint: Refer to
3. Why will inhibition of ATP synthesis by a cell lead eventually to a decrease Table 4.3.
and, ultimately, cessation in secondary active transport? Hint: See Figure 4.13, 8. By what mechanism might an increase in intracellular Na+ concentration
and refer to Figure 4.11 for a reminder about primary active transport. lead to an increase in exocytosis? Hint: See Figure 4.15 for help.
4. Given the following solutions, which has the lowest water concentration? Which
two have the same osmolarity? Hint: Refer to Figures 4.16 and 4.17 for help.
Solute Concentration (mM)
Solution Glucose Urea NaCl CaCl2
A 20 30 150 10
B 10 100 20 50
C 100 200 10 20
D 30 10 60 100

CHAPTER 4 T E ST QU E ST I ONS General Principles Assessment Answers appear in Appendix A.

These questions reinforce the key theme first introduced in Chapter 1, that general principles of physiology can be applied across all
levels of organization and across all organ systems.

1. How does the information presented in Figures 4.8–4.10 and 4.17 illustrate 3. Another general principle states that physiological processes are dictated
the general principle that homeostasis is essential for health and survival? by the laws of chemistry and physics. How does this relate to the movement
2. Give two examples from this chapter that illustrate the general principle that of solutes through lipid bilayers and its dependence on electrochemical
controlled exchange of materials occurs between compartments and across gradients? How is heat related to solute movement?
cellular membranes.

Movement of Solutes and Water Across Cell Membranes 117