Transport of Substances Through the Cell Membrane pdf - Membrane Physiology and Nerve and Muscle

means random molecular movement of substances molecule by molecule, either

Although there are many variations of these basic mechanisms, diffusion

directly through the lipid bilayer or through the proteins, occurs by one of two

Transport through the cell membrane, either

“Diffusion” Versus “Active Transport.”

of molecules or ions that are allowed to cross the membrane.

the interstices of the protein to the other side of the membrane. Both the

bind with molecules or ions that are to be transported; confor-

carrier proteins,

Others, called

channel proteins.

selected ions or molecules; these are called

Different proteins function differently. Some have watery spaces all

proteins.

brane. Most of these penetrating proteins, therefore, can function as

the lipid bilayer, constituting an alternative pathway through the cell mem-

transporting substances. Their molecular structures interrupt the continuity of

The protein molecules in the membrane have entirely different properties for

as described later.

through the lipid substance itself; this is true mainly of lipid-soluble substances,

most arrow, a few substances can penetrate this lipid bilayer, diffusing directly

lular fluid compartments. However, as demonstrated in Figure 4–2 by the left-

molecules and water-soluble substances between the extracellular and intracel-

cellular fluid. Therefore, it constitutes a barrier against movement of water

The lipid bilayer is not miscible with either the extracellular fluid or the intra-

membrane, as shown in Figure 4–2.

protein molecules in the lipid, many of which penetrate all the way through the

lipid bilayer,

is discussed in Chapter 2 and illustrated in Figures 2–3 and 4–2. This membrane

The structure of the membrane covering the outside of every cell of the body

and Cell Membrane Transport Proteins

mechanisms of the cell membranes.

differences are extremely important to the life of the cell. The purpose of this

cellular fluid are considerably greater than those in the extracellular fluid. These

tains very little. But the concentrations of phosphates and proteins in the intra-

of chloride ions, whereas the intracellular fluid con-

Also, the extracellular fluid contains a large amount

Figure 4–1 gives the approximate concentrations of

Transport of Substances Through

the Cell Membrane

important electrolytes and other substances in the
extracellular fluid and intracellular fluid. Note that
the extracellular fluid contains a large amount of
sodium but only a small amount of potassium.
Exactly the opposite is true of the intracellular fluid.

chapter is to explain how the differences are brought about by the transport

The Lipid Barrier of the Cell Membrane,

consists almost entirely of a

but it also contains large numbers of

transport

the way through the molecule and allow free movement of water as well as

mational changes in the protein molecules then move the substances through

channel proteins and the carrier proteins are usually highly selective in the types

basic processes: diffusion or active transport.

through intermolecular spaces in the membrane or in combination with a carrier

The rate of diffusion is determined by the amount of

interaction with carrier proteins in the membrane.

large size.

similar manner, except that the colloids diffuse far

Ions diffuse in the same manner as whole molecules,

times each second. This continual movement of mole-

another, and so forth, randomly bouncing thousands of

molecules first in one direction, then another, then

kinetic energy. Thus, as shown in Figure 4–3, a single

while molecule A slows down, losing some of its

sequently, molecule B gains kinetic energy of motion,

energy of motion of molecule A to molecule B. Con-

molecule A repel molecule B, transferring some of the

cule, B, the electrostatic and other nuclear forces of

a moving molecule, A, approaches a stationary mole-

condition except at absolute zero temperature. When

“heat”—the greater the motion, the higher the tem-

way. Motion of these particles is what physicists call

stant motion, each particle moving its own separate

water molecules and dissolved substances, are in con-

All molecules and ions in the body fluids, including

Diffusion

processes.

energy. Following is a more detailed explanation of

state to a high-concentration state. This movement

an energy gradient, such as from a low-concentration

By contrast, active transport means movement of

of the normal kinetic motion of matter.

protein. The energy that causes diffusion is the energy

Membrane Physiology, Nerve, and Muscle

Unit II

ions or other substances across the membrane in com-
bination with a carrier protein in such a way that the
carrier protein causes the substance to move against

requires an additional source of energy besides kinetic

the basic physics and physical chemistry of these two

perature—and the motion never ceases under any

molecule in a solution bounces among the other

cules among one another in liquids or in gases is called
diffusion.

and even suspended colloid particles diffuse in a

less rapidly than molecular substances because of their

Diffusion Through the Cell Membrane

Diffusion through the cell membrane is divided into
two subtypes called simple diffusion and facilitated
diffusion. Simple diffusion means that kinetic move-
ment of molecules or ions occurs through a membrane
opening or through intermolecular spaces without any

(40 mEq/ L)

(5 mEq/ L)

0.5 g/dl-------------- 2 to 95 g/dl

2 mEq/L

75 mEq/ L

10 mEq/ L

4 mEq/ L

58 mEq/ L

0.0001 mEq/ L

140 mEq/ L

10 mEq/ L

1 mEq/L -------------

4 mEq/ L -------------

28 mEq/ L -----------

103 mEq/ L ---------

1.2 mEq/ L ----------

2.4 mEq/ L ----------

4 mEq/ L ------------

142 mEq/ L ---------

---------------

-----------------

--------------

–

----------------

HCO

–

-----------

Phosphates-----

– -------------

Glucose ---------

Amino acids ----

90 mg/dl ------------

30 mg/dl ------------

0 to 20 mg/dl

200 mg/dl ?

Cholesterol

Phospholipids

Neutral fat

---------------

PCO

-------------

pH -----------------

Proteins ----------

35 mm Hg ---------

46 mm Hg ---------

7.4 -------------------

2 g/dl ----------------

20 mm Hg ?

50 mm Hg ?

7.0

16 g/dl

EXTRACELLULAR

FLUID

INTRACELLULAR

FLUID

Figure 4–1

Chemical compositions of extracellular and intracellular fluids.

Diffusion

diffusion

Channel

protein

Simple

Facilitated

Energy

Active transport

Carrier proteins

mechanisms of transport.

Transport pathways through the cell membrane, and the basic

Figure 4–2

Diffusion of a fluid molecule during a thousandth of a second.

Figure 4–3

tive force is pulling ions into the channels, and the

bonds are different. Therefore, no strong attrac-

they are not negatively charged,

the sodium channels, only 0.3 by 0.3 nanometer, but

of Figure 4–4. These channels are slightly smaller than

tive for potassium transport, shown in the lower panel

Conversely, another set of protein channels is selec-

selective for passage of sodium ions.

of diffusion. Thus, the sodium channel is specifically

molecules. Once in the channel, the sodium ions

sodium ions into these channels, actually pulling

These strong negative charges can pull small

the channel proteins in the top panel of Figure 4–4.

tively charged,

0.3 by 0.5 nanometer in diameter, but more important,

sodium channel,

protein channels, the so-called

To give an example, one of the most important of the

charges and chemical bonds along its inside surfaces.

its diameter, its shape, and the nature of the electrical

from the characteristics of the channel itself, such as

one or more specific ions or molecules. This results

gates.

stances, and (2) many of the channels can be opened

are distinguished by two important characteristics: (1)

of the membrane to the other. The protein channels

lar fluid. Therefore, substances can move by simple

through the membrane within minutes.

the astonishing rate of water penetration, this amount

about 1000 times less than that of water. Even so, given

molecule is only 20 per cent greater than that of water,

off rapidly. For instance, the diameter of the urea

However, as they become larger, their penetration falls

great as the volume of the red cell itself.

astounding. As an example, the total amount of water

through the membrane. The rapidity with which water

in the membrane lipids, it readily passes through chan-

Diffusion of Water and Other Lipid-Insoluble Molecules Through

therefore, oxygen can be delivered to the interior of

proportional to its lipid solubility. Especially large

For obvious reasons, the rate of diffusion of each of

carbon dioxide, and alcohols are high, so that all these

instance, the lipid solubilities of oxygen, nitrogen,

of the substance. For

Diffusion of Lipid-Soluble Substances Through the Lipid Bilayer.

proteins, as shown to the left in Figure 4–2.

soluble, and (2) through watery channels that pene-

brane by two pathways: (1) through the interstices of

protein. The carrier protein aids passage of the mole-

Facilitated diffusion requires interaction of a carrier

through which the molecules or ions can move.

substance available, the velocity of kinetic motion, and

Transport of Substances Through the Cell Membrane

Chapter 4

the number and sizes of openings in the membrane

cules or ions through the membrane by binding
chemically with them and shuttling them through the
membrane in this form.

Simple diffusion can occur through the cell mem-

the lipid bilayer if the diffusing substance is lipid

trate all the way through some of the large transport

One of the most important factors that determines
how rapidly a substance diffuses through the lipid
bilayer is the lipid solubility

can dissolve directly in the lipid bilayer and diffuse
through the cell membrane in the same manner that
diffusion of water solutes occurs in a watery solution.

these substances through the membrane is directly

amounts of oxygen can be transported in this way;

the cell almost as though the cell membrane did not
exist.

Protein Channels.

Even though water is highly insoluble

nels in protein molecules that penetrate all the way

molecules can move through most cell membranes is

that diffuses in each direction through the red cell
membrane during each second is about 100 times as

Other lipid-insoluble molecules can pass through

the protein pore channels in the same way as water
molecules if they are water soluble and small enough.

yet its penetration through the cell membrane pores is

of urea penetration still allows rapid transport of urea

Diffusion Through Protein Channels,
and “Gating” of These Channels

Computerized three-dimensional reconstructions of
protein channels have demonstrated tubular pathways
all the way from the extracellular to the intracellu-

diffusion directly along these channels from one side

they are often selectively permeable to certain sub-

or closed by

Selective Permeability of Protein Channels.

Many of the

protein channels are highly selective for transport of

is only

the inner surfaces of this channel are strongly nega-

as shown by the negative signs inside

dehy-

drated
the sodium ions away from their hydrating water

diffuse in either direction according to the usual laws

and their chemical

potassium ions are not pulled away from the water

Gate

closed

Gate open

Outside

Inside

Gate

closed

Gate open

Outside

Inside

–

–
–

–

to open or close “gates” guarding the channels.

Also shown are conformational changes in the protein molecules

Transport of sodium and potassium ions through protein channels.

Figure 4–4

milliseconds. This demonstrates the rapidity with

snaps open and then snaps closed, each open state

either “all or none.” That is, the gate of the channel

membrane. Note that the channel conducts current

teristic of most voltage-gated channels. This figure

Figure 4–5

Open-State Versus Closed-State of Gated Channels.

than this diameter to pass through. This gate is

of this channel, providing a negatively charged pore

acetylcholine channel.

ligand gating.

chemical gating

protein molecule that opens or closes the gate. This

substance (a ligand) with the protein; this causes a

Chemical (ligand) gating.

action potential, as is discussed more fully in

becomes positively charged. The opening of these

intracellular ends of the potassium channels, and

of Figure 4–4, the potassium gates are on the

responsible for nerve signals. In the bottom panel

sodium pores. This is the basic mechanism for

membrane loses its negative charge, these gates

tightly closed; conversely, when the inside of the

on the inside of the cell membrane, this presumably

4–4, when there is a strong negative charge

membrane. For instance, in the top panel of Figure

In this instance, the molecular

Voltage gating.

The opening and closing of gates are controlled in

the shape of the protein molecule itself.

extensions of the transport protein molecule, which

for selective gating of sodium and potassium ions. It is

channels. This is shown in both panels of Figure 4–4

larger hydrated sodium ions are rejected, thus provid-

can pass easily through this small channel, whereas the

sium. Therefore, the smaller hydrated potassium ions

molecules that hydrate them. The hydrated form of

Membrane Physiology, Nerve, and Muscle

Unit II

the potassium ion is considerably smaller than the
hydrated form of sodium because the sodium ion
attracts far more water molecules than does potas-

ing selective permeability for a specific ion.

Gating of Protein Channels.

Gating of protein channels

provides a means of controlling ion permeability of the

believed that some of the gates are actual gatelike

can close the opening of the channel or can be lifted
away from the opening by a conformational change in

two principal ways:

conformation of the gate or of its chemical bonds
responds to the electrical potential across the cell

could cause the outside sodium gates to remain

would open suddenly and allow tremendous
quantities of sodium to pass inward through the

eliciting action potentials in nerves that are

they open when the inside of the cell membrane

gates is partly responsible for terminating the

Chapter 5.

Some protein channel

gates are opened by the binding of a chemical

conformational or chemical bonding change in the

is called

One of

the most important instances of chemical gating
is the effect of acetylcholine on the so-called

Acetylcholine opens the gate

about 0.65 nanometer in diameter that allows
uncharged molecules or positive ions smaller

exceedingly important for the transmission of nerve
signals from one nerve cell to another (see Chapter
45) and from nerve cells to muscle cells to cause
muscle contraction (see Chapter 7).

A shows an especially interesting charac-

shows two recordings of electrical current flowing
through a single sodium channel when there was an
approximate 25-millivolt potential gradient across the

lasting for only a fraction of a millisecond up to several

To recorder

Milliseconds

Open sodium channel

Picoamperes

Recorder

Membrane

“patch”

torn away from the cell.

To the right, recording is from a membrane patch that has been

recording is performed from a “patch” of a living cell membrane.

ing current flow through a single protein channel. To the left,

The “patch-clamp” method for record-

Record of current flow through a single voltage-gated sodium

Figure 4–5

A,
channel, demonstrating the “all or none” principle for opening and
closing of the channel. B,

Figure 4–7. This figure shows a carrier protein with a

What is it that limits the rate of facilitated diffusion?

diffusion, the rate of diffusion cannot rise greater than

increase proportionately, but in the case of facilitated

increases, the rate of simple diffusion continues to

fusion is demonstrated in Figure 4–6. The figure shows

concentration of the diffusing substance increases. This

, as the

diffusion approaches a maximum, called V

ing substance, in facilitated diffusion the rate of

the following important way: Although the rate of

Facilitated diffusion differs from simple diffusion in

of the substance to the other side.

protein to help. That is, the carrier

carrier-mediated dif-

Facilitated diffusion is also called

properties.

across the membrane, one can determine the transport

concentrations of different ions, as well as the voltage

in the membrane patch being studied. By varying the

a given voltage.

the membrane can be set at will—that is, “clamped” to

as desired. Also, the voltage between the two sides of

This allows the concentrations of ions both inside the

can be torn away from the cell. The pipette with

Alternatively, as shown to the right in Figure 4–5

membrane “patch” at the tip of the pipette through

pipette touch the cell membrane. The result is a minute

of the pipette. This creates a seal where the edges of the

the outside of a cell membrane. Then suction is applied

diameter of only 1 or 2 micrometers, is abutted against

Very simply, a micropipette, having a tip

in Figure 4–5

achieved by using the “patch-clamp” method illustrated

This has been

protein channels as shown in Figure 4–5

gates tend to snap open and closed intermittently,

At in-between voltages, as shown in the figure, the

level, it may remain open either all or most of the time.

or almost all the time, whereas at another voltage

potential, the channel may remain closed all the time

closing of the protein molecular gates. At one voltage

Because the binding force of the receptor is weak, the

pore now opens to the opposite side of the membrane.

cal change occurs in the carrier protein, so that the

in a fraction of a second, a conformational or chemi-

transported enters the pore and becomes bound. Then,

the inside of the protein carrier. The molecule to be

partway through. It also shows a binding “receptor” on

Transport of Substances Through the Cell Membrane

Chapter 4

pore large enough to transport a specific molecule

thermal motion of the attached molecule causes it to
break away and to be released on the opposite side of

which changes can occur during the opening and

giving an average current flow somewhere between
the minimum and the maximum.

Patch-Clamp Method for Recording Ion Current Flow Through
Single Channels.

One might wonder how it is technically

possible to record ion current flow through single

inside the pipette to pull the membrane against the tip

which electrical current flow can be recorded.

the small cell membrane patch at the end of the pipette

its sealed patch is then inserted into a free solution.

micropipette and in the outside solution to be altered

It has been possible to make such patches small

enough so that only a single channel protein is found

characteristics of the single channel and also its gating

Facilitated Diffusion

fusion because a substance transported in this manner
diffuses through the membrane using a specific carrier

facilitates diffusion

simple diffusion through an open channel increases
proportionately with the concentration of the diffus-

max

difference between simple diffusion and facilitated dif-

that as the concentration of the diffusing substance

the V

max

level.

A probable answer is the mechanism illustrated in

Facilitated diffusion

Simple diffusion

Concentration of substance

Rate of diffusion

max

shows that facilitated diffusion approaches a maximum rate called

a membrane by simple diffusion and facilitated diffusion. This

Effect of concentration of a substance on rate of diffusion through

Figure 4–6

the V

max

Transported

molecule

Binding point

Carrier protein

and

conformational

change

Release
of binding

Postulated mechanism for facilitated diffusion.

Figure 4–7

times, considerable pressure difference develops

side 2. This equation is extremely important in under-

concentration on side 1, and C

between side 1 and side 2 of the membrane, C

determined from the following formula, called the

body temperature (37°C), the electrical difference

enough, the two effects balance each other. At normal

right. When the concentration difference rises high

ference now tends to move the ions to the left, while

electrical potential difference. The concentration dif-

of Figure 4–8

right, creating the condition shown in the right panel

net diffusion occurs from left to right.After much time,

whereas the negative charge repels them. Therefore,

brane. The positive charge attracts the negative ions,

the left, creating an electrical gradient across the mem-

brane, but a positive charge has been applied to the

the left panel of Figure 4–8

tration difference exists to cause movement. Thus, in

applied across the membrane, as shown in Figure

tration inside.

the concentration on the inside, or:

Therefore, the rate of net diffusion into the cell is pro-

the membrane.

outward

the outside of the membrane each second. Conversely,

outside,

inward

concentration on the inside. The rate at which the sub-

Figure 4–8

factors.

direction. This net rate is determined by several

through the cell membrane. What is usually important

Factors That Affect Net Rate

in the body, as discussed in Chapter 78.

glucose as much as 10-fold to 20-fold. This is the prin-

similar to that of glucose, including galactose. Also,

molecular weight of about 45,000; it can also transport

carrier molecule has been discovered, and it has a

In the case of glucose, the

amino acids.

“diffuse”—in either direction through the membrane.

allows the transported molecule to move—that is, to

states. Note specifically, though, that this mechanism

the membrane. The rate at which molecules can be

Membrane Physiology, Nerve, and Muscle

Unit II

transported by this mechanism can never be greater
than the rate at which the carrier protein molecule
can undergo change back and forth between its two

Among the most important substances that cross

cell membranes by facilitated diffusion are glucose and
most of the

several other monosaccharides that have structures

insulin can increase the rate of facilitated diffusion of

cipal mechanism by which insulin controls glucose use

of Diffusion

By now it is evident that many substances can diffuse

is the net rate of diffusion of a substance in the desired

Effect of Concentration Difference on Net Diffusion Through a
Membrane.

A shows a cell membrane with a

substance in high concentration on the outside and low

stance diffuses

is proportional to the con-

centration of molecules on the

because this

concentration determines how many molecules strike

the rate at which molecules diffuse

is propor-

tional to their concentration inside

portional to the concentration on the outside minus

Net diffusion

µ (C

- C

)

in which C

is concentration outside and C

is concen-

Effect of Membrane Electrical Potential on Diffusion of Ions—
The “Nernst Potential.”

If an electrical potential is

4–8B, the electrical charges of the ions cause them to
move through the membrane even though no concen-

B, the concentration of

negative ions is the same on both sides of the mem-

right side of the membrane and a negative charge to

large quantities of negative ions have moved to the

B, in which a concentration difference of

the ions has developed in the direction opposite to the

the electrical difference tends to move them to the

that will balance a given concentration difference of
univalent ions—such as sodium (Na

) ions—can be

Nernst equation:

in which EMF is the electromotive force (voltage)

is the

is the concentration on

standing the transmission of nerve impulses and is dis-
cussed in much greater detail in Chapter 5.

Effect of a Pressure Difference Across the Membrane.

EMF in millivolts

61 log

(

)

= ±

- -

–

- -

- - -

–

Outside

Inside

Membrane

Piston

cause diffusion of molecules and ions through a cell membrane.

, and pressure difference

ence affecting negative ions

, electrical potential differ-

Effect of concentration difference

Figure 4–8

(A)

(B)

(C) to

than small particles, move at slower velocities (v). The

That is, large particles, which have greater mass (m)

the same amount of pressure against the membrane.

in a solution, regardless of its mass, exerts, on average,

the particles. The reason for this is that each particle

not by the mass

are molecules or ions, is determined by the

sure exerted by particles in a solution, whether they

The osmotic pres-

nondiffusible solute.

enough to oppose the osmotic effect. The pressure dif-

farther apart, until eventually a pressure difference

water from chamber B into chamber A causes the

that will not penetrate the membrane. Osmosis of

uid, one containing pure water and the

10, which shows

osmosis is demonstrated in Figure 4

The principle of a pressure difference opposing

would be slowed, stopped, or even reversed. The exact

chloride solution, osmosis of water into this solution

If in Figure 4

Osmotic Pressure

that is,

the water concentration has been reduced. Thus, net

where there is pure water, than on the right side, where

water molecules strike the channels on the left side,

9, more

water. As a result, in the example of Figure 4

ions are present and, therefore, has reduced the con-

so to sodium and chloride ions. Yet the presence of the

ant sodium and chloride ions, and the membrane is

culty. Therefore, sodium chloride solution is actually a

pass through the cell membrane with ease, whereas

sodium chloride on the other side. Water molecules

9, with pure water on

conditions shown in Figure 4

To give an example of osmosis, let us assume the

osmosis.

ment. This process of net movement of water caused

shrink, depending on the direction of the water move-

cell membrane, causing the cell either to swell or to

happens, net movement of water does occur across the

differences for other substances can occur. When this

can develop across a membrane, just as concentration

certain conditions, a

volume of the cell remains constant. However, under

movement of water occurs. Therefore, the

normally,

Yet,

volume of the cell itself.

through the cell membrane is water. Enough water

of Water

Net Diffusion

Osmosis Across Selectively

to the other side.

the pore on this side and, therefore, more molecules to

pore,

This effect is demonstrated in Figure 4

the high-pressure side toward the low-pressure side.

side. The result is that increased amounts of energy are

greater than on the other side. In most instances, this

on one side of a membrane than on the other, this

a given instant. Therefore, when the pressure is higher

20 mm Hg greater inside the capillary than outside.

brane in all tissues of the body. The pressure is about

This occurs, for instance, at the blood capillary mem-

between the two sides of a diffusible membrane.

Transport of Substances Through the Cell Membrane

Chapter 4

Pressure actually means the sum of all the forces of

the different molecules striking a unit surface area at

means that the sum of all the forces of the molecules
striking the channels on that side of the membrane is

is caused by greater numbers of molecules striking the
membrane per second on one side than on the other

available to cause net movement of molecules from

–8C, which

shows a piston developing high pressure on one side
of a “

” thereby causing more molecules to strike

“diffuse”

Permeable Membranes—
“

”

By far the most abundant substance that diffuses

ordinarily diffuses in each direction through the red
cell membrane per second to equal about 100 times the

the amount that

diffuses in the two directions is balanced so precisely
that zero net

concentration difference for water

by a concentration difference of water is called

–

one side of the cell membrane and a solution of

sodium and chloride ions pass through only with diffi-

mixture of permeant water molecules and nonperme-

said to be selectively permeable to water but much less

sodium and chloride has displaced some of the water
molecules on the side of the membrane where these

centration of water molecules to less than that of pure

–

movement of water occurs from left to right—
osmosis occurs from the pure water into the sodium
chloride solution.

–9 pressure were applied to the sodium

amount of pressure required to stop osmosis is called
the osmotic pressure of the sodium chloride solution.

–

a selectively permeable membrane separating two
columns of fl
other containing a solution of water and any solute

levels of the fluid columns to become farther and

develops between the two sides of the membrane great

ference across the membrane at this point is equal to
the osmotic pressure of the solution that contains the

Importance of Number of Osmotic Particles (Molar Concentra-
tion) in Determining Osmotic Pressure.

number of

particles per unit volume of fluid,

small particles move at higher velocities in such a way

Water

NaCl solution

Osmosis

Figure 4–9

Osmosis at a cell membrane when a sodium chloride solution is
placed on one side of the membrane and water is placed on the
other side.

lality of 1 milliosmole per kilogram. The normal

in each kilogram of water

Thus, a solution that has

58.5 grams, is equal to 2 osmoles.

ciated, 1 gram molecular weight of sodium chloride,

the nondissociated solute. Therefore, when fully disso-

ions, 1 gram molecular weight of the solute will

into ions. Conversely, if a solute dissociates into two

is 1 gram molecular weight of glucose, is equal to 1

cally active solute. Thus, 180 grams of glucose, which

is used in place of grams.

of a solution in terms of numbers of particles, the unit

To express the concentration

ciated molecule), not in terms of mass of the solute.

particle. Consequently, the factor that determines the

that their average kinetic energies (k), determined by

Membrane Physiology, Nerve, and Muscle

Unit II

the equation

are the same for each small particle as for each large

osmotic pressure of a solution is the concentration of
the solution in terms of number of particles (which is
the same as its molar concentration if it is a nondisso-

“Osmolality”—The Osmole.

called the osmole

One osmole is 1 gram molecular weight of osmoti-

osmole of glucose because glucose does not dissociate

become 2 osmoles because the number of osmotically
active particles is now twice as great as is the case for

1 osmole of solute dissolved

is said to have an osmolality

of 1 osmole per kilogram, and a solution that has
1/1000 osmole dissolved per kilogram has an osmo-

ferent sugars, and most of the amino acids.

ions, chloride ions, iodide ions, urate ions, several dif-

ions, potassium ions, calcium ions, iron ions, hydrogen

sure gradient), the process is called

ions to the outside of cells. When a cell membrane

two sides of the membrane. Instead, some energy

effects could occur by simple diffusion, because simple

is especially true for sodium ions. Neither of these two

uid are great. This

versely, it is important to keep the concentrations of

This is true, for instance, for potassium ions. Con-

At times, a large concentration of a substance is

Substances Through

“Active Transport” of

studies.

lality, this is the usual practice in almost all physiologic

larity and osmolality are less than 1 per cent. Because it

the body, the quantitative differences between osmo-

osmotic pressure, for dilute solutions such as those in

used instead. Although, strictly speaking, it is osmoles

rather than osmoles per kilogram of water, is

osmolarity,

to determine osmolality,

uring kilograms of water in a solution, which is required

The Term “Osmolarity.”

culated value.

potential. Therefore, on average, the actual osmotic

consequently, they cannot move entirely unrestrained

and chloride ions, are highly attracted to one another;

uids, such as sodium

about 5500 mm Hg. The reason for this difference is

The measured value for this, however, averages only

uids of 5790 mm Hg.

osmotic pressure.

solution. Likewise,

C, a concentration of 1 osmole per

temperature, 37

300 milliosmoles per kilogram of water.

osmolality of the extracellular and intracellular fluids
is about

Relation of Osmolality to Osmotic Pressure.

At normal body

liter will cause 19,300 mm Hg osmotic pressure in the

1 milliosmole per liter concentra-

tion is equivalent to 19.3 mm Hg
Multiplying this value by the 300 milliosmolar con-
centration of the body fluids gives a total calculated
osmotic pressure of the body fl

that many of the ions in the body fl

in the fluids and create their full osmotic pressure

pressure of the body fluids is about 0.93 times the cal-

Because of the difficulty of meas-

which is the

osmolar concentration expressed as osmoles per liter of
solution

per kilogram of water (osmolality) that determines

is far more practical to measure osmolarity than osmo-

Membranes

required in the intracellular fluid even though the
extracellular fluid contains only a small concentration.

other ions very low inside the cell even though their
concentrations in the extracellular fl

diffusion eventually equilibrates concentrations on the

source must cause excess movement of potassium ions
to the inside of cells and excess movement of sodium

moves molecules or ions “uphill” against a concentra-
tion gradient (or “uphill” against an electrical or pres-

active transport.

Different substances that are actively transported

through at least some cell membranes include sodium

diffusible

Water

Semipermeable

membrane

Non-

solute

permeable membrane.

Demonstration of osmotic pressure caused by osmosis at a semi-

Figure 4–10

to the interior of the cell. Unless this is checked, the

potassium, sodium, and other positive ions as well. All

cannot escape from the cell. Most of these are nega-

the volume is as follows: Inside the cell are large

swell until they burst. The mechanism for controlling

function of this pump, most cells of the body would

pump is to control the volume of each cell. Without

Pump for Controlling Cell Volume.

out of

energy

nerve cells, 60 to 70 per cent of the cells

reaction. For some cells, such as electrically active

, determine the direction of the enzyme

phosphate, as well as the electrochemical gradients for

cell. The relative concentrations of ATP, ADP, and

produce ATP or use the energy to change its confor-

therefore, can either donate its phosphate to ADP to

pump,

phate. The phosphorylated form of the Na

pump will synthesize ATP from ADP and phos-

the chemical energy of ATP hydrolysis, these ions will

can run in reverse. If the electrochemical gradients for

ATPase pump

As with other enzymes, the Na

sium ions to the inside.

change in the protein carrier molecule, extruding the

phosphate bond of energy. This liberated energy is

cleaves one molecule of ATP, splitting it to adenosine

function of the protein becomes activated. This then

and three sodium ions bind on the inside, the ATPase

To put the pump into perspective: When two potas-

binding sites has ATPase activity.

3. The inside portion of this protein near the sodium

outside.

2. It has two

1. It has three

ular weight of about 55,000. Although the function of

subunit, with a molec-

subunit, with a molecular weight of about 100,000,

two separate globular proteins: a larger one called the

pump. The

Figure 4

the basis of nerve function, transmitting nerve signals

cells. Indeed, Chapter 5 shows that this pump is also

differences across the cell membrane, as well as for

the outside to the inside. This pump is responsible for

pump, a transport process that pumps

The active transport mechanism that has been

hydrogen, chloride, and a few other ions.

active transport are sodium, potassium, calcium,

Primary Active Transport

transport, with more detailed explanations of their

chemical gradient. Following are some examples

However, in active transport, the carrier protein func-

cell membrane, as is true for facilitated diffusion.

primary active transport. In both instances, transport

two sides of a cell membrane, created originally by

pound. In secondary active transport, the energy is

(ATP) or of some other high-energy phosphate com-

In primary active transport, the energy is derived

Primary Active Transport and Secondary Active Transport.

Transport of Substances Through the Cell Membrane

Chapter 4

Active transport is divided into two types according to
the source of the energy used to cause the transport:
primary active transport and secondary active trans-
port.
directly from breakdown of adenosine triphosphate

derived secondarily from energy that has been stored
in the form of ionic concentration differences of
secondary molecular or ionic substances between the

depends on carrier proteins that penetrate through the

tions differently from the carrier in facilitated diffu-
sion because it is capable of imparting energy to the
transported substance to move it against the electro-

of primary active transport and secondary active

principles of function.

Sodium-Potassium Pump

Among the substances that are transported by primary

studied in greatest detail is the sodium-potassium
(Na

-K

)

sodium ions outward through the cell membrane of all
cells and at the same time pumps potassium ions from

maintaining the sodium and potassium concentration

establishing a negative electrical voltage inside the

throughout the nervous system.

–11 shows the basic physical components of

the Na

-K

carrier protein is a complex of

a
and a smaller one called the

the smaller protein is not known (except that it might
anchor the protein complex in the lipid membrane),
the larger protein has three specific features that are
important for the functioning of the pump:

receptor sites for binding sodium ions

on the portion of the protein that protrudes to the
inside of the cell.

receptor sites for potassium ions on the

sium ions bind on the outside of the carrier protein

diphosphate (ADP) and liberating a high-energy

then believed to cause a chemical and conformational

three sodium ions to the outside and the two potas-

-K

and K

are experimentally increased enough so

that the energy stored in their gradients is greater than

move down their concentration gradients and the Na

-K

mation and pump Na

out of the cell and K

into the

and K

’

requirement may be devoted to pumping Na

the cell and K

into the cell.

Importance of the Na

-K

One of the most important functions of the Na

-K

numbers of proteins and other organic molecules that

tively charged and therefore attract large numbers of

these molecules and ions then cause osmosis of water

ATPase

ATP

Inside

Outside

ADP

3Na

adenosine diphosphate; ATP, adenosine triphosphate; Pi,

Postulated mechanism of the sodium-potassium pump. ADP,

Figure 4–11

phosphate ion.

to be co-transported. Once they both are attached, the

brane. The carrier in this instance serves as an attach-

a coupling mechanism is required. This is achieved by

For sodium to pull another substance along with it,

form of

brane.This phenomenon is called

diffuse to the interior. Under appropriate conditions,

very low concentration inside. This gradient represents

primary active transport, a large concentration gradi-

When sodium ions are transported out of cells by

Co-Transport and Counter-Transport

Secondary Active Transport

alone.

renal tubules and many glandular cells, expend as

can be tremendous. Some cells, such as those lining the

2800 calories. One can see that the energy expenditure

is about 1400 calories; or to concentrate it 100-fold,

Thus, in terms of calories, the amount of energy

is concentrated, as expressed by the following

In other words, the energy required is proportional

it 1000-fold requires three times as much energy.

requires twice as much energy, and to concentrate

trate a substance 10-fold, to concentrate it 100-fold

port. Compared with the energy required to concen-

The amount of energy required to transport a sub-

Energetics of Primary Active Transport

uids. The hydrogen ions can be secreted into the

port. In this case, large amounts of hydrogen ions are

the gastric gland parietal cells, the hydrogen ion con-

stomach digestive secretions. At the secretory ends of

This is the basis for secreting hydrochloric acid in the

transporting hydrogen ions of any part of the body.

In the gastric glands, the deep-lying

and cortical collecting ducts of the kidneys.

glands of the stomach, and (2) in the late distal tubules

hydrogen ions is very important: (1) in the gastric

At two places in the body, primary active transport of

Primary Active Transport of Hydrogen Ions

carrier protein. The difference is that this protein has

capability to cleave ATP as the ATPase of the sodium

and functions as an enzyme ATPase, having the same

instances, the carrier protein penetrates the membrane

and the mitochondria in all cells. In each of these

cell, such as the sarcoplasmic reticulum of muscle cells

the cell. The other pumps calcium ions into one or

primary active transport calcium pumps. One is in the

uid. This is achieved mainly by two

intracellular cytosol of virtually all cells in the body, at

calcium pump.

Primary Active Transport of Calcium Ions

bers for transmitting nerve and muscle signals.

membrane. As discussed in Chapter 5, this electrical

Therefore, the Na

inside the cell; that is, it causes negativity on the inside.

the exterior for each cycle of the pump. This creates pos-

The fact that the

veillance role in maintaining normal cell volume.

Therefore, the Na

pump, moving still more

If a cell begins to swell for any reason, this auto-

net loss of ions out of the cell, which initiates osmosis

strong tendency to stay there. Thus, this represents a

once the sodium ions are on the outside, they have a

able to sodium ions than to potassium ions, so that

to the interior. Also, the membrane is far less perme-

pump.

nitely until it bursts. The normal

Membrane Physiology, Nerve, and Muscle

Unit II

cell will swell indefi
mechanism for preventing this is the Na

-K

Note again that this device pumps three Na

ions to

the outside of the cell for every two K

ions pumped

of water out of the cell as well.

matically activates the Na

-K

ions to the exterior and carrying water with them.

-K

pump performs a continual sur-

Electrogenic Nature of the Na

-K

Pump.

-K

pump moves three Na

ions to the exterior for

every two K

ions to the interior means that a net of one

positive charge is moved from the interior of the cell to

itivity outside the cell but leaves a deficit of positive ions

-K

pump is said to be electrogenic

because it creates an electrical potential across the cell

potential is a basic requirement in nerve and muscle
fi

Another important primary active transport mecha-
nism is the

Calcium ions are normally

maintained at extremely low concentration in the

a concentration about 10,000 times less than that in the
extracellular fl

cell membrane and pumps calcium to the outside of

more of the intracellular vesicular organelles of the

a highly specific binding site for calcium instead of for
sodium.

parietal cells

have the most potent primary active mechanism for

centration is increased as much as a millionfold and
then released into the stomach along with chloride
ions to form hydrochloric acid.

In the renal tubules are special intercalated cells in

the late distal tubules and cortical collecting ducts that
also transport hydrogen ions by primary active trans-

secreted from the blood into the urine for the purpose
of eliminating excess hydrogen ions from the body
fl
urine against a concentration gradient of about
900-fold.

stance actively through a membrane is determined by
how much the substance is concentrated during trans-

to the logarithm of the degree that the substance

formula:

required to concentrate 1 osmole of substance 10-fold

for concentrating substances in cells or for removing
substances from cells against a concentration gradient

much as 90 per cent of their energy for this purpose

—

ent of sodium ions across the cell membrane usually
develops—high concentration outside the cell and

a storehouse of energy because the excess sodium
outside the cell membrane is always attempting to

this diffusion energy of sodium can pull other sub-
stances along with the sodium through the cell mem-

co-transport; it is one

secondary active transport.

means of still another carrier protein in the cell mem-

ment point for both the sodium ion and the substance

energy gradient of the sodium ion causes both the
sodium ion and the other substance to be transported
together to the interior of the cell.

Energy in calories per osmole

1400 log

(

)

across these membranes, which in turn causes osmosis

This creates a high sodium ion concentration gradient

the surrounding connective tissue and blood vessels.

and lateral membranes of the cells, sodium ions are

lumen into the interior of the cell. Then, at the basal

Therefore, sodium and water diffuse readily from the

the cells is permeable to both sodium ions and water.

The brush border on the luminal surfaces of

kisses.

intestines, gallbladder, and renal tubules. This

Figure 4

in the sheet, and then (2) either

The basic mechanism for transport of a substance

other membranes.

exocrine glands, (4) epithelium of the gallbladder, and

epithelium of the renal tubules, (3) epithelium of all

type occurs through the (1) intestinal epithelium, (2)

simply through the cell membrane. Transport of this

At many places in the body, substances must be trans-

Active Transport Through

Chapter 30.

uids, as discussed in detail in

of hydrogen ions,

tubules, but it can transport extremely

concentrating hydrogen ions, counter-transport is not

transported into the tubule lumen. As a mechanism for

of the tubular cell, while hydrogen ions are counter-

of the kidneys, where sodium ions

proximal tubules

several tissues. An especially important example is in

Sodium-hydrogen counter-transport occurs in

transport of calcium that occurs in some cells.

transport mode. This is in addition to primary active

both bound to the same transport protein in a counter-

moving to the interior and calcium ions to the exterior,

all or almost all cell membranes, with sodium ions

Sodium-calcium counter-transport occurs through

sodium-hydrogen counter-transport.

sodium-calcium counter-transport

Two especially important counter-transport mecha-

Hydrogen Ions

Sodium Counter-Transport of Calcium and

iodine ions, iron ions, and urate ions.

least some cells include co-transport of chloride ions,

blood, as is discussed in later chapters.

c molecular characteristics.

ed, each of which is

ferent set of transport proteins. Five

same manner as for glucose, except that it uses a dif-

cell at the same time. Hence, this is a

formational change takes place automatically, and the

attaches. When they both become attached, the con-

inside, which provides energy for the transport. A

sodium and one for glucose. Also, the concentration of

has two binding sites on its exterior side, one for

12. Note that the transport carrier protein

in Figure 4

mechanism of this is entirely by co-transport, as shown

most cells against large concentration gradients; the

Co-Transport of Glucose and Amino Acids

exterior.

have bound, a conformational change occurs, and

interior projection of the carrier protein. Once both

the substance to be counter-transported binds to the

jects to the exterior surface of the membrane, while

must be transported to the outside. Therefore, the

concentration gradient. However, this time, the sub-

counter-transport,

Transport of Substances Through the Cell Membrane

Chapter 4

sodium ions again attempt to

diffuse to the interior of the cell because of their large

stance to be transported is on the inside of the cell and

sodium ion binds to the carrier protein where it pro-

energy released by the sodium ion moving to the
interior causes the other substance to move to the

Along with Sodium Ions

Glucose and many amino acids are transported into

–

sodium ions is very high on the outside and very low

special property of the transport protein is that a con-
formational change to allow sodium movement to the
interior will not occur until a glucose molecule also

sodium and glucose are transported to the inside of the

sodium-glucose

co-transport mechanism.

Sodium co-transport of the amino acids occurs in the

amino acid trans-

port proteins have been identifi
responsible for transporting one subset of amino acids
with specifi

Sodium co-transport of glucose and amino acids

occurs especially through the epithelial cells of the
intestinal tract and the renal tubules of the kidneys to
promote absorption of these substances into the

Other important co-transport mechanisms in at

nisms (transport in a direction opposite to the primary
ion) are

and

the
move from the lumen of the tubule to the interior

nearly as powerful as the primary active transport of
hydrogen ions that occurs in the more distal renal

large numbers

thus making it a key to hydrogen

ion control in the body fl

Cellular Sheets

ported all the way through a cellular sheet instead of

(5) membrane of the choroid plexus of the brain and

through a cellular sheet is (1) active transport through
the cell membrane on one side of the transporting cells

simple diffusion or

facilitated diffusion through the membrane on the
opposite side of the cell.

–13 shows a mechanism for transport

of sodium ions through the epithelial sheet of the

figure

shows that the epithelial cells are connected together
tightly at the luminal pole by means of junctions called
“

”

actively transported into the extracellular fluid of

Na-binding

site

Glucose

Glucose-binding
site

Postulated mechanism for sodium co-transport of glucose.

Figure 4–12

Rev 80:211, 2000.

Russell JM: Sodium-potassium-chloride cotransport. Physiol

Rev Physiol 64:877, 2002.

action between genetic and environmental factors. Annu

sodium channel and the control of sodium balance: inter-

Rossier BC, Pradervand S, Schild L, Hummler E: Epithelial

exchange molecule: an overview. Ann N Y Acad Sci 976:1,

Philipson KD, Nicoll DA, Ottolia M, et al: The Na

porters. News Physiol Sci 19:80, 2004.

Peres A, Giovannardi S, Bossi E, Fesce R: Electrophysiolog-

MacKinnon R: Potassium channels. FEBS Lett 555:62, 2003.

a shared structure. Physiol Rev 82:735, 2002.

degenerin family of ion channels: a variety of functions for

Kellenberger S, Schild L: Epithelial sodium channel/

Physiol Rev 82:769, 2002.

Kaupp UB, Seifert R: Cyclic nucleotide-gated ion channels.

Physiol Rev 82:503, 2002.

structure and physiological function of chloride channels.

Jentsch TJ, Stein V, Weinreich F, Zdebik AA: Molecular

channels. Pharmacol Rev 55:607, 2003.

Dolphin AC: G protein modulation of voltage-gated calcium

Annu Rev Physiol 62:919, 2000.

De Weer P: A century of thinking about cell membranes.

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Decoursey TE: Voltage-gated proton channels and other

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Caplan MJ: Ion pump sorting in polarized renal epithelial

family of ion channels. J Physiol 520:631, 1999.

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Agre P, Kozono D: Aquaporin water channels: molecular

different types of transport discussed in this chapter.

Throughout this text are numerous examples of the

ltrate by the renal tubules.

the blood from the intestine; they are also the way the

nutrients, ions, and other substances are absorbed into

These are the mechanisms by which almost all the

transport not only of sodium ions but also of water.

of water as well. Thus, active transport of sodium ions

Membrane Physiology, Nerve, and Muscle

Unit II

at the basolateral sides of the epithelial cells results in

same substances are reabsorbed from the glomerular
fi

References

degenerin/epithelial sodium channel (Deg/ENaC) super-

ical insights into the mechanism of ion-coupled cotrans-

/Ca

2002.

Diffusion

Active

transport

Brush

border

Basement

membrane

Connective tissue

Osmosis

Lumen

Active

transport

Active

transport

Osmosis

and
H

Basic mechanism of active transport across a layer of cells.

Figure 4–13