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Chapter TWELVE
12
Membrane Transport
Cells live and grow by exchanging molecules with their environment.
The plasma membrane acts as a barrier that controls the transit of
molecules into and out of the cell. Because the interior of the lipid bilayer
is hydrophobic, as we saw in Chapter 11, the plasma membrane tends
to block the passage of almost all water-soluble molecules. But various
water-soluble molecules must be able to cross the plasma membrane:
cells must import nutrients such as sugars and amino acids, eliminate
metabolic waste products such as CO2, and regulate the intracellular
concentrations of a variety of inorganic ions. A few of these solutes,
CO2 and O2 for example, can simply diffuse across the lipid bilayer, but
the vast majority cannot. Instead, their transfer depends on specialized
membrane transport proteins that span the lipid bilayer, providing
private passageways across the membrane for select substances (Figure
12–1).
In this chapter, we consider how membranes control the traffic of small
molecules into and out of cells. Cells can also selectively transfer macromolecules such as proteins across their membranes, but this transport
requires more elaborate machinery and is discussed in Chapter 15. Here,
we begin by outlining some of the general principles that guide the passage of small, water-soluble molecules through cell membranes. We then
examine, in turn, the two main classes of membrane proteins that mediate this transfer. A transporter, which has moving parts, can shift small
molecules from one side of the membrane to the other by changing its
shape. Solutes transported in this way can be either small organic molecules or inorganic ions. Channels, in contrast, form tiny hydrophilic pores
in the membrane through which solutes can pass by diffusion. Most channels let through inorganic ions only and are therefore called ion channels.
PRINCIPLES OF MEMBRANE
TRANSPORT
TRANSPORTERS AND THEIR
FUNCTIONS
ION CHANNELS AND THE
MEMBRANE POTENTIAL
ION CHANNELS AND
SIGNALING IN NERVE CELLS
388
Chapter 12
Membrane transport
Figure 12–1 Specialized membrane
transport proteins are responsible
for transferring small water-soluble
molecules across cell membranes.
Whereas protein-free artificial lipid bilayers
are impermeable to most water-soluble
molecules (a), cell membranes are not (B).
Note that each type of transport protein in a
cell membrane transfers a particular type of
molecule, causing a selective set of solutes
to end up inside the membrane-enclosed
compartment.
(A) protein-free
artificial lipid bilayer
(B) cell membrane
Because these ions are electrically charged, their movements can create powerful electric forces
the membrane. In the final part of the
ECB3 across
E12.01/12.01
chapter, we discuss how these forces enable nerve cells to communicate,
ultimately carrying out the astonishing range of behaviors of which the
human brain is capable.
PRINCIPLES OF MEMBRANE TRANSPORT
To provide a foundation for discussing membrane transport, we first consider the differences in ion composition between a cell’s interior and its
environment. This will help make it clear why the transport of ions by
both transporters and ion channels is of such fundamental importance
to cells.
The Ion Concentrations Inside a Cell Are Very Different
from Those Outside
Living cells maintain an internal ion composition that is very different
from the ion composition in the fluid around them, and these differences
are crucial for a cell’s survival and function. Inorganic ions such as Na+,
K+, Ca2+, Cl–, and H+ (protons) are the most plentiful of all the solutes in
a cell’s environment, and their movements across cell membranes play
an essential part in many biological processes, including the activity of
nerve cells, as we discuss later in this chapter, and the production of ATP
by all cells, as we discuss in Chapter 14.
Na+ is the most plentiful positively charged ion (cation) outside the cell,
while K+ is the most plentiful inside (Table 12–1). For a cell to avoid being
TabLE 12–1 a CoMpariSon of ion ConCEnTraTionS inSidE and ouTSidE a TypiCaL MaMMaLian CELL
CoMponEnT
inTraCELLuLar ConCEnTraTion (mM)
ExTraCELLuLar ConCEnTraTion (mM)
Na+
5–15
145
K+
140
5
Mg2+
0.5
1–2
Ca2+
10–4
1–2
h+
7 ¥ 10–5 (10–7.2 M or ph 7.2)
4 ¥ 10–5 (10–7.4 M or ph 7.4)
5–15
110
Cations
Anions*
Cl–
* the cell must contain equal quantities of positive and negative charges (that is, be electrically neutral). thus, in addition to Cl–,
the cell contains many other anions not listed in this table; in fact, most cellular constituents are negatively charged (hCO3–, pO43–,
proteins, nucleic acids, metabolites carrying phosphate and carboxyl groups, etc.). the concentrations of Ca2+ and Mg2+ given are
for the free ions. there is a total of about 20 mM Mg2+ and 1–2 mM Ca2+ in cells, but this is mostly bound to proteins and other
substances and, for Ca2+, stored within various organelles.
principles of Membrane transport
389
torn apart by electrical forces, the quantity of positive charge inside the
cell must be balanced by an almost exactly equal quantity of negative
charge there, and the same is true for the charge in the surrounding fluid.
However, tiny excesses of positive or negative charge, concentrated in
the neighborhood of the plasma membrane, do occur, and they have
important electrical effects, as we discuss later. The high concentration
of Na+ outside the cell is balanced chiefly by extracellular Cl–. The high
concentration of K+ inside is balanced by a variety of negatively charged
intracellular ions (anions).
This differential distribution of ions inside and outside the cell is controlled
in part by the activity of membrane transport proteins and in part by the
permeability characteristics of the lipid bilayer itself.
Lipid Bilayers Are Impermeable to Solutes and Ions
The hydrophobic interior of the lipid bilayer creates a barrier to the passage of most hydrophilic molecules, including ions. They are as reluctant
to enter a fatty environment as hydrophobic molecules are reluctant
to enter water. But given enough time, virtually any molecule will diffuse across a lipid bilayer. The rate at which it diffuses, however, varies
enormously depending on the size of the molecule and its solubility properties. In general, the smaller the molecule and the more soluble it is in
oil (that is, the more hydrophobic, or nonpolar, it is), the more rapidly it
will diffuse across. Thus:
1. Small nonpolar molecules, such as molecular oxygen (O2, molecular
mass 32 daltons) and carbon dioxide (44 daltons), readily dissolve
in lipid bilayers and therefore rapidly diffuse across them; indeed,
cells require this permeability to gases for the cell respiration processes discussed in Chapter 14.
2. Uncharged polar molecules (molecules with an uneven distribution of electric charge) also diffuse rapidly across a bilayer, if they
are small enough. Water (18 daltons) and ethanol (46 daltons), for
example, cross fairly rapidly; glycerol (92 daltons) crosses less rapidly; and glucose (180 daltons) crosses hardly at all (Figure 12–2).
3. In contrast, lipid bilayers are highly impermeable to all ions and
charged molecules, no matter how small. The molecules’ charge
and their strong electrical attraction to water molecules inhibit
them from entering the hydrocarbon phase of the bilayer. Thus,
synthetic bilayers are a billion (109) times more permeable to water
than they are to even such small ions as Na+ or K+.
Cell membranes allow water and small nonpolar molecules to permeate
by simple diffusion. But for cells to take up nutrients and release wastes,
membranes must also allow the passage of many other molecules, such
as ions, sugars, amino acids, nucleotides, and many cell metabolites.
These molecules cross lipid bilayers far too slowly by simple diffusion;
thus, specialized membrane transport proteins are required to transfer
them efficiently across cell membranes.
Membrane Transport Proteins Fall into Two Classes:
Transporters and Channels
Membrane transport proteins occur in many forms and in all types of biological membranes. Each protein provides a private passageway across
the membrane for a particular class of molecule—ions, sugars, or amino
acids, for example. Most of these protein portals are even more exclusive, allowing entrance of only select members of a particular molecular
class: some, for example, are open to Na+ but not K+, others to K+ but
not Na+. The set of membrane transport proteins present in the plasma
O2
SMALL
CO2
HYDROPHOBIC
N2
MOLECULES
benzene
SMALL
UNCHARGED
POLAR
MOLECULES
H2O
glycerol
ethanol
LARGER
UNCHARGED
POLAR
MOLECULES
amino acids
glucose
nucleosides
IONS
H+, Na+
HCO3-, K+
Ca2+, CIMg2+
synthetic
lipid
bilayer
Figure 12–2 The rate at which a molecule
diffuses across a synthetic lipid bilayer
depends on its size and solubility. the
smaller the molecule and, more importantly,
the ECB3
fewer its
favorable interactions with
E12.02/12.02
water (that is, the less polar it is), the more
rapidly the molecule diffuses across the
bilayer. Note that many of the molecules
that the cell uses as nutrients are too large
and polar to pass through a pure lipid
bilayer.
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Chapter 12
Membrane transport
solute
ion
lipid
bilayer
solute-binding site
(A) TRANSPORTER
Figure 12–3 Small molecules and ions can
enter the cell through a transporter or
a channel. (a) a transporter undergoes a
series of conformational changes to transfer
small water-soluble molecules across the
lipid bilayer. (B) a channel, in contrast,
forms a hydrophilic pore across the bilayer
through which specific inorganic ions or
in some cases other small molecules can
diffuse. as would be expected, channels
transfer molecules at a much greater rate
than transporters. Ion channels can exist in
either an open or a closed conformation,
and they transport only in the open
conformation, which is shown here. Channel
opening and closing is usually controlled by
an external stimulus or by conditions within
the cell.
(B) CHANNEL PROTEIN
membrane or in the membrane of an intracellular organelle determines
exactly which solutes can pass into and out of that cell or organelle. Each
type of membrane therefore has its own characteristic set of transport
proteins.
As discussed in Chapter 11, the membrane transport proteins that have
been studied in detail have polypeptide chains that traverse the lipid
bilayer multiple times—that is, they are multipass transmembrane proteins (see Figure 11–24). By crisscrossing back and forth across the
bilayer, the polypeptide chain forms a continuous protein-lined pathway
that allows selected small hydrophilic molecules to cross the membrane
without coming into direct contact with the hydrophobic interior of the
ECB3 m11.03/12.03
lipid bilayer.
Membrane transport proteins can be divided into two main classes:
transporters and channels. The basic difference between transporters
and channels is the way they discriminate between solutes, transporting
some solutes but not others (Figure 12–3). Channels discriminate mainly
on the basis of size and electric charge: if a channel is open, an ion or a
molecule that is small enough and carries the appropriate charge can slip
through, as through a narrow trapdoor. A transporter, on the other hand,
allows passage only to those molecules or ions that fit into a binding
site on the protein; it then transfers these molecules across the membrane one at a time by changing its own conformation, acting more like
a turnstile than an open door. Transporters bind their solutes with great
specificity in the same way that an enzyme binds its substrate, and it is
this requirement for specific binding that makes the transport selective.
Solutes Cross Membranes by Passive or Active Transport
Transporters and channels allow small molecules to cross the cell membrane, but what controls whether these solutes move into the cell or out
of it? In many cases, the direction of transport depends on the relative
concentrations of the solute. Molecules will spontaneously flow ‘downhill’ from a region of high concentration to a region of low concentration,
provided a pathway exists. Such movements are called passive, because
they need no other driving force. If, for example, a solute is present at
a higher concentration outside the cell than inside and an appropriate
channel or transporter is present in the plasma membrane, the solute
will move spontaneously across the membrane down its concentration
gradient into the cell by passive transport (sometimes called facilitated
diffusion), without expenditure of energy by its membrane transport protein. All channels and many transporters act as conduits for such passive
transport.
To move a solute against its concentration gradient, however, a membrane transport protein must do work: it has to drive the flow ‘uphill’
by coupling it to some other process that provides energy (as discussed
in Chapter 3 for enzyme reactions). Transmembrane solute movement
transporters and their Functions
transported molecule
channel
transporter
concentration
gradient
lipid
bilayer
EN
ER
G
simple
diffusion
channelmediated
Y
transportermediated
PASSIVE TRANSPORT
ACTIVE TRANSPORT
Figure 12–4 Most solutes cross cell
membranes by passive or active
transport. Some small uncharged
molecules can move down their
concentration gradient across the lipid
bilayer by simple diffusion. But most
solutes require the assistance of a channel
or transporter. as indicated, movement of
molecules in the same direction as their
concentration gradient—passive transport—
occurs spontaneously, whereas transport
against a concentration gradient—active
transport—requires an input of energy. Only
transporters can carry out active transport,
but both transporters and channels can
carry out passive transport.
driven in this way is termed active transport, and it is carried out only
by special types of transporters that can harness some energy source to
the transport process (Figure 12–4). Because they drive the transport of
solutes against their concentration gradient, many of these transporters
are called pumps. We now examine a variety of transporters, both active
and passive, and see how they function to move molecules across cell
membranes.
TRANSPORTERS AND THEIR FUNCTIONS
Transporters are required for the movement of almost all small organic
molecules across cell membranes, with the exception of fat-soluble molecules and small uncharged molecules that can pass directly through
the lipid bilayer by simple diffusion (see Figure 12–2). Each transporter is
highly selective, often transferring just one type of molecule. To guide and
propel the complex traffic of small molecules into and out of the cell, and
between the cytosol and the different membrane-enclosed organelles,
each cellular membrane contains
set of different transporters approECB3 am11.04a/12.04
priate to that particular membrane. For example, the plasma membrane
contains transporters that import nutrients such as sugars, amino acids,
and nucleotides; the lysosome membrane contains an H+ transporter that
acidifies the lysosome interior; and the inner membrane of mitochondria
contains transporters for importing the pyruvate that mitochondria use
as fuel for generating ATP and for exporting ATP once it is synthesized
(Figure 12–5).
Although the detailed molecular mechanisms that underlie the movement
of solutes are known for only a few transporters, the general principles
that govern the function of these proteins are well understood.
nucleotide
sugar
amino acid
Na
+
+
H
pyruvate
lysosome
ATP
mitochondrion
plasma membrane
391
Figure 12–5 Each cell membrane has its
own characteristic set of transporters.
392
Chapter 12
Membrane transport
Figure 12–6 a conformational change in
a transporter could mediate the passive
transport of a solute such as glucose.
In this model, the transporter can exist in
two conformational states: in state a the
binding sites for the solute are exposed on
the outside of the membrane; in state B the
same sites are exposed on the other side of
the membrane. the transition between the
two states is proposed to occur randomly
and independently of whether the solute
is bound and to be completely reversible.
If the concentration of the solute is higher
on the outside of the membrane, it will be
more often caught up in a Æ B transitions
that carry it into the cell than in B Æ a
transitions that carry it out. there will
therefore be a net transport of the solute
down its concentration gradient.
solute
OUTSIDE
concentration
gradient
lipid
bilayer
INSIDE
transporter mediating
passive transport
solute-binding site
state A
state B
Concentration Gradients and Electrical Forces Drive
Passive Transport
Solutes can cross the membrane by passive or active transport—and
transporters are capable of facilitating both types of movement (see Figure
12–4). A simple example of a transporter that mediates passive transport
is the glucose transporter found in the plasma membrane of mammalian
liver cells and many other cell types. The protein consists of a polypeptide
ECB3 m11.05/12.06
chain that crosses the membrane at least 12 times. It is thought that the
transporter can adopt at least two conformations and switches reversibly and randomly between them. In one conformation, the transporter
exposes binding sites for glucose to the exterior of the cell; in the other, it
exposes these sites to the interior of the cell (Figure 12–6).
Question 12–1
A simple enzyme reaction can be
described by the equation E + S 
ES Æ E + P, where E is the enzyme,
S the substrate, P the product, and
ES the enzyme–substrate complex.
A. Write a corresponding equation
describing the workings of a
transporter (T) that mediates the
transport of a solute (S) down its
concentration gradient.
B. What does this equation tell you
about the function of a transporter?
C. Why would this equation be an
inappropriate description of channel
function?
?
When sugar is plentiful outside a liver cell, as it is after a meal, glucose
molecules bind to the transporter’s externally displayed binding sites;
when the protein switches conformation, it carries these molecules
inward and releases them into the cytosol, where the glucose concentration is low. Conversely, when blood sugar levels are low—when you
are hungry—the hormone glucagon stimulates the liver cell to produce
large amounts of glucose by the breakdown of glycogen. As a result, the
glucose concentration is higher inside the cell than outside, and glucose
binds to any internally displayed binding sites on the transporter; when
the protein switches conformation in the opposite direction, the glucose
is transported out of the cell. The flow of glucose can thus go either way,
according to the direction of the glucose concentration gradient across
the membrane: inward if glucose is more concentrated outside the cell
than inside, and outward if the opposite is true. Transporters of this type,
which permit a flux of solute but play no part in determining its direction, carry out passive transport. Although passive, the transport is highly
selective: the binding sites in the glucose transporter bind only d-glucose
and not, for example, its mirror image l-glucose, which the cell cannot
use for glycolysis.
For glucose, which is an uncharged molecule, the direction of passive
transport is determined solely by its concentration gradient. For electrically charged molecules, either small organic ions or inorganic ions, an
additional force comes into play. For reasons we explain later, most cell
membranes have a voltage across them, a difference in the electrical
potential on each side of the membrane, which is referred to as the membrane potential. This difference in potential exerts a force on any molecule
that carries an electric charge. The cytoplasmic side of the plasma membrane is usually at a negative potential relative to the outside, and this
tends to pull positively charged solutes into the cell and drive negatively
charged ones out. At the same time, a charged solute will also tend to
move down its concentration gradient.
transporters and their Functions
The net force driving a charged solute across the membrane is therefore
a composite of two forces, one due to the concentration gradient and the
other due to the voltage across the membrane. This net driving force is
called the electrochemical gradient for the given solute. This gradient
determines the direction of passive transport across the membrane. For
some ions, the voltage and concentration gradient work in the same direction, creating a relatively steep electrochemical gradient (Figure 12–7A).
This is the case for Na+, which is positively charged and at a higher concentration outside cells than inside. Na+ therefore tends to enter cells if
given an opportunity. If, however, the voltage and concentration gradients have opposing effects, the resulting electrochemical gradient can
be small (Figure 12–7B). This is the case for K+, a positively charged ion
that is present at a much higher concentration inside cells than outside.
Because of these opposing effects, K+ has a small electrochemical gradient across the membrane, despite its large concentration gradient, and
therefore there is little net movement of K+ across the membrane.
Active Transport Moves Solutes Against Their
Electrochemical Gradients
Of course, cells cannot rely solely on passive transport. Active transport
of solutes against their electrochemical gradient is essential to maintain
the intracellular ionic composition of cells and to import solutes that are
at a lower concentration outside the cell than inside. Cells carry out active
transport in three main ways (Figure 12–8): (i) Coupled transporters couple
the uphill transport of one solute across the membrane to the downhill
transport of another. (ii) ATP-driven pumps couple uphill transport to the
hydrolysis of ATP. (iii) Light-driven pumps, which are found mainly in bacterial cells, couple uphill transport to an input of energy from light, as
discussed for bacteriorhodopsin (see Figure 11–28).
(A)
(B)
+
+ + +
+ + +
OUTSIDE
+++
+++
+++
+
+
–––
– ––
INSIDE
+
electrochemical
gradient when voltage
and concentration
gradients work in
the same direction
393
+
+++
–––
– ––
+ +
+
+
+ +
+ +
+
electrochemical
gradient when voltage
and concentration
gradients work in
opposite directions
Figure 12–7 an electrochemical gradient
has two components. the net driving
force (the electrochemical gradient) tending
to move a charged solute (ion) across a
membrane is the sum of the concentration
gradient of the solute and the voltage
across a membrane (the membrane
potential, which is represented here by
the + and – signs at the membrane). the
width of the green arrow represents the
magnitude of the electrochemical gradient
for a positively charged solute in two
different situations. In (a), the concentration
gradient is supplemented by a membrane
potential that increases the driving force.
In (B), the ECB3
membrane
potential acts against
m11.04b/12.07
the concentration gradient, decreasing the
driving force for movement of the solute.
Because a substance has to be carried uphill before it can flow downhill,
the different forms of active transport are necessarily linked. Thus, in
the plasma membrane of an animal cell, an ATP-driven pump transports
Na+ out of the cell against its electrochemical gradient, and this Na+ can
then flow back in, down its electrochemical gradient. Because the ion
flows through Na+-coupled transporters, the influx of Na+ provides an
energy source that drives the active movement of many other substances
into the cell against their electrochemical gradients. If the Na+ pump
ceased operating, the Na+ gradient would soon run down, and transport
through Na+-coupled transporters would come to a halt. The ATP-driven
Na+ pump, therefore, has a central role in membrane transport in animal
cells. In plant cells, fungi, and many bacteria, a similar role is played by
ATP-driven H+ pumps that create an electrochemical gradient of H+ ions
by pumping H+ out of the cell, as we discuss later.
LIGHT
electrochemical
gradient
ATP
COUPLED
TRANSPORTER
ADP + Pi
ATP-DRIVEN
PUMP
LIGHT-DRIVEN
PUMP
Figure 12–8 Cells drive active transport in
three main ways. the actively transported
molecule is shown in yellow, and the energy
source is shown in red.