Republic of the Philippines

NUEVA VIZCAYA STATE UNIVERSITY

Bayombong, Nueva Vizcaya
INSTRUCTIONAL MODULE
IM No.: IM-BIO8-1ST SEM- 2021-2022

COLLEGE OF ARTS AND SCIENCES

Bayombong Campus

DEGREE PROGRAM BS BIOLOGY COURSE NO. BIO 8

SPECIALIZATION MICRO/MB COURSE TITLE CELL AND MOLECULAR BIOLOGY
YEAR LEVEL 3 TIME FRAME WK NO. IM NO.

I. CHAPTER III: THE CELL SURFACE AND EXTRACELLULAR MATRIX

II. LESSON TITLE:

Membrane Transport

III. LESSON OVERVIEW

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 module 3, 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 1).

Figure 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.

In this module, 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. 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

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through which solutes can pass by diffusion. Most channels let through inorganic ions only and are therefore
called ion channels.

Because these ions are electrically charged, their movements can create powerful electric forces across the
membrane. In the final part of the module, 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.

IV. DESIRED LEARNING OUTCOMES

1. Relate the structure of membranes to its function.

2. Explain the significance of membranes.

IV. LESSON CONTENT

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 module.

Na+ is the most plentiful positively charged ion (cation) outside the cell, while K+ is the most plentiful inside (Table
1). For a cell to avoid being 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).
Table 1. A comparison of ion concentrations inside and outside a typical mammalian cell

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
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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.
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+.

Figure 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 fewer its
favorable interactions with 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.

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 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.
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Figure 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.

As discussed in module 3, 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. 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 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 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.

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Figure 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.

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 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 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. 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 a set of different transporters
appropriate 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 5).

Figure 5. Each cell membrane has its own

characteristic set of transporters.

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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.

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 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 6).

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.

Figure 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.

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

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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.

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 7). 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 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.

Figure 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 membrane potential acts against the concentration gradient,
decreasing the driving force for movement of the solute.

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 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.

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Figure 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.

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.

Animal Cells Use the Energy of ATP Hydrolysis to Pump Out Na +

The ATP-driven Na+ pump in animal cells hydrolyzes ATP to ADP to transport Na+ out of the cell; this pump is
therefore not only a transporter, but also an enzyme—an ATPase. At the same time, the protein couples the
outward transport of Na+ to an inward transport of K+. The pump is therefore commonly known as the Na+-K+
ATPase, or the Na+-K+ pump (Figure 9).

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Figure 9. The na+-K+ pump plays a central role in membrane transport in animal cells. this
transporter uses the energy of ATP hydrolysis to pump Na+ out of the cell and K+ in, both
against their electrochemical gradients, although the electrochemical gradient for K+ is close
to zero.

This transporter plays a central part in the energy economy of animal cells, typically accounting for 30% or more
of their total ATP consumption. Like a bilge pump in a leaky ship, it operates ceaselessly to expel the Na+ that
is constantly entering through other transporters and ion channels. In this way, the pump keeps the Na+
concentration in the cytosol about 10–30 times lower than in the extracellular fluid and the K+ concentration
about 10–30 times higher. Under normal conditions, the interior of most cells is at a negative electric potential
compared with the exterior, so that positive ions tend to be pulled into the cell. This means that the inward
electrochemical driving force for Na+ is large, as it includes the driving force due to the concentration gradient
and a driving force in the same direction due to the voltage gradient (see Figure 7A).

Figure 10. Na+ outside the cell is like water behind a high
dam. The water in the dam has potential energy, which can be
used to drive energy-requiring processes. In the same way,
an ion gradient across a membrane can be used to drive
active processes in a cell, including the active transport of
other molecules.

The Na+ outside the cell, on the uphill side of its electrochemical gradient, is like a large volume of water behind
a high dam: it represents a very large store of energy Figure 10). Even if one artificially halts the operation of the
Na+-K+ pump with a toxin such as the plant glycoside ouabain, the energy in this store is sufficient to sustain for
many minutes the other transport processes that are driven by the downhill flow of Na+.

For K+ the situation is different. The electric force is the same as for Na+, because it depends only on the charge
carried by the ion. The concentration gradient, however, is in the opposite direction. The result, under normal
conditions, is that the net driving force for movement of K+ across the membrane is close to zero: the electric
force pulling K+ into the cell is almost exactly balanced by the concentration gradient tending to drive it out.

The Na+-K+ Pump Is Driven by the Transient Addition of a Phosphate Group

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The Na+-K+ pump provides a beautiful illustration of how a protein couples one reaction to another, following
the principles discussed in Chapter 3. The pump works in a cycle, as illustrated schematically in Figure 11. Na+
binds to the pump at sites exposed inside the cell (stage 1), activating the ATPase activity. ATP is split, with the
release of ADP and the transfer of a phosphate group into a high-energy linkage to the pump itself—that is, the
pump phosphorylates itself (stage 2).

Figure 11. The Na+-K+ pump transports ions in a cyclic manner. The binding of cytosolic Na+ (1) and the
subsequent phosphorylation by ATP of the cytosolic face of the pump (2) induce the protein to undergo a
conformational change that transfers the Na+ across the membrane and releases it on the outside (3). The
high energy linkage of the phosphate to the protein provides the energy to drive the conformational change.
The binding of K+ on the extracellular surface (4) and the subsequent dephosphorylation (5) return the protein
to its original conformation, which transfers the K+ across the membrane and releases it into the cytosol (6).
The changes in conformation are analogous to the A ↔ B transitions, except that here the Na+-dependent
phosphorylation and the K+-dependent dephosphorylation of the protein cause the conformational transitions
to occur in an orderly manner, enabling the protein to do useful work. For simplicity, only one Na+- and one
K+-binding site are shown. In the real pump in mammalian cells, there are thought to be three Na+- and two
K+-binding sites. the net result of one cycle of the pump is therefore to transport three Na+ out of the cell and
two K+ in. Ouabain inhibits the pump by preventing K+ binding.

Phosphorylation causes the pump to switch its conformation so as to release Na+ at the exterior surface of the
cell and, at the same time, to expose a binding site for K+ at the same surface (stage 3). The binding of
extracellular K+ (stage 4) triggers the removal of the phosphate group (stage 5), causing the pump to switch
back to its original conformation, discharging the K+ into the cell interior (stage 6). The whole cycle, which takes
about 10 milliseconds, can then be repeated. Each step in the cycle depends on the one before, so that if any of
the individual steps is prevented from occurring, all the functions of the pump are halted. This tight coupling
ensures that the pump operates only when the appropriate ions are available to be transported, thereby avoiding
useless ATP hydrolysis.

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The Na+-K+ Pump Helps Maintain the Osmotic Balance of Animal Cells

The plasma membrane is permeable to water (see Figure 12), and if the total concentration of solutes is low on
one side of the membrane and high on the other, water will tend to move across it until the solute concentrations
are equal. The movement of water from a region of low solute concentration (high water concentration) to a
region of high solute concentration (low water concentration) is called osmosis. Cells contain specialized water
channels (called aquaporins) in their plasma membrane that facilitate this flow. The driving force for the water
movement is equivalent to a difference in water pressure and is called the osmotic pressure. In the absence of
any counteracting pressure, the osmotic movement of water into a cell will cause it to swell (Figure 12).

Figure 12. The diffusion of water is known as osmosis. If the concentration of

solutes inside a cell is higher than that outside, water will move in by osmosis,
causing the cell to swell. If a cell is placed in a high-salt solution, however, water will
rush out

In the tissues of the animal body, cells are bathed by a fluid that is rich in solutes, especially Na+ and Cl–. This
balances the concentration of organic and inorganic solutes confined inside the cell. But the osmotic balance is
always in danger of being upset, as the external solutes are constantly leaking into the cell down their individual
electrochemical gradients. Animal cells thus have to do continuous work, pumping out unwanted solutes to
maintain the osmotic equilibrium (Figure 13A). This function is performed mainly by the Na+-K+ pump, which
pumps out the Na+ that leaks in. At the same time, the Na+-K+ pump helps to maintain a membrane potential
(as we explain later). This membrane potential tends to prevent the entry of Cl–, which is negatively charged and
would need to move against the electrical gradient generated by the pump to enter the cell

Figure 13. Cells use different tactics to avoid

osmotic swelling. The animal cell keeps the
intracellular solute concentration low by pumping
out ions (a). The plant cell’s tough wall prevents
swelling (B). The protozoan avoids swelling by
periodically ejecting the water that moves into the
cell (C).

Different cells cope with osmotic challenges in different ways. Plant cells are prevented from swelling by their
tough cell walls and so can tolerate a large osmotic difference across their plasma membrane (Figure 13B).
The cell wall exerts a counteracting pressure that tends to balance the osmotic pressure created by the solutes
in the cell and thereby limits the movement of water into the cell. Osmosis, together with the active transport of
ions into the cell, results in a turgor pressure that keeps plant cells distended with water, with their cell wall tense.
Thus, plant cells are like footballs, in which a leather outer case is held taut by the pressure in the pumped-up
rubber bladder inside; the cell wall acts like the leather outer case, and the plasma membrane acts like the rubber
bladder. The turgor pressure serves various functions. It holds plant stems rigid and leaves extended. It also
plays a part in regulating gas exchange through the stomata— the microscopic ‘mouths’ in the surface of a leaf;

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these pores are opened and closed by the guard cells that surround them (Figure 14). Guard cells control their
own turgor pressure by regulating the movement of K+ across their plasma membranes.

Figure 14. Stomata open on the underside of a leaf. The opening and
closing of these pores is controlled by the sausage-shaped guard cells
that surround them.

In some protozoans living in fresh water, such as amoebae, the excess water that continually flows into the cell
by osmosis is collected in contractile vacuoles that periodically discharge their contents to the exterior (Figure
13C). The cell first allows the vacuole to fill with a solution rich in solutes, which causes water to follow by
osmosis. The cell then retrieves the solutes by actively pumping them back into the cytosol before emptying the
vacuole to the exterior.

Intracellular Ca2+ Concentrations Are Kept Low by Ca2+ Pumps

Ca2+, like Na+, is also kept at a low concentration in the cytosol compared with its concentration in the
extracellular fluid, but it is much less plentiful than Na+, both inside and outside cells. The movement of Ca2+
across cell membranes, however, is crucially important because Ca2+ can bind tightly to a variety of proteins in
the cell, altering their activities. An influx of Ca2+ into the cytosol through Ca2+ channels, for example, is often
used as a signal to trigger other intracellular events, such as the secretion of signal molecules and the contraction
of muscle cells.

The lower the background concentration of free Ca2+ in the cytosol, the more sensitive the cell is to an increase
in cytosolic Ca2+. Thus, eukaryotic cells in general maintain very low concentrations of free Ca2+ in their cytosol
(about 10–4 mM) in the face of very much higher extracellular Ca2+ concentrations (typically 1–2 mM). This
huge concentration difference is achieved mainly by means of ATP-driven Ca2+ pumps in both the plasma
membrane and the endoplasmic reticulum membrane, which actively pump Ca2+ out of the cytosol.

Like the Na+-K+ pump, the Ca2+ pump is an ATPase that is phosphorylated and dephosphorylated during its
pumping cycle (Figure 15). It is thought to work in much the same way as depicted for the Na+-K+ pump in
Figure 11 except that it returns to its original conformation without binding and transporting a second ion. These
two ATP-driven pumps have similar amino acid sequences and structures, suggesting that they share a common
evolutionary origin.

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Figure 15. A Ca2+ pump returns Ca2+ to the sarcoplasmic reticulum in a skeletal muscle
cell. The three-dimensional structure of this membrane transport protein has been
determined by X-ray crystallography and electron microscopy. The calcium pump is a
single protein composed of four discrete domains with different functions. When a muscle
cell is stimulated, Ca2+ floods from the sarcoplasmic reticulum—a specialized form of
endoplasmic reticulum—into the cytosol, allowing the cell to contract; to recover from the
contraction, Ca2+ is returned to the sarcoplasmic reticulum by this Ca2+ pump. The
polypeptide chain of the protein crosses the membrane as 10 α helices. ATP binding and
the consequent phosphorylation of an aspartic acid in the transporter trigger
conformational changes that bring the nucleotide-binding and activator domains into close
proximity. This movement in turn leads to a rearrangement of the transmembrane helices,
which eliminates the Ca2+-binding sites and releases Ca2+ ions into the lumen of the
sarcoplasmic reticulum. Note that the pathway Ca2+ ions take through the protein allows
the ions to avoid contact with the lipid bilayer.

Coupled Transporters Exploit Gradients to Take Up Nutrients Actively

A gradient of any solute across a membrane, like the Na+ gradient generated by the Na+-K+ pump, can be used
to fuel the active transport of a second molecule. The downhill movement of the first solute down its gradient
provides the energy to drive the uphill transport of the second. The transporters that do this are called coupled
transporters (see Figure 8). They may couple the movement of one inorganic ion to that of another, the
movement of an inorganic ion to that of an organic molecule, or the movement of one organic molecule to that
of another. If the transporter moves both solutes in the same direction across the membrane, it is called a symport
(Figure 16). If it moves them in opposite directions, it is called an antiport. A transporter that ferries only one type
of solute across the membrane (and is therefore not a coupled transporter) is called a uniport. The passive
glucose transporter described earlier (see Figure 6) is a uniport

Figure 16. Some transporters carry a single solute across

the membrane (uniports); others couple the uphill transport
of one solute across to the downhill transport of another. In
coupled transport, the solutes can be transferred either in the
same direction, by symports, or in the opposite direction, by
antiports. Uniports, symports, and antiports are used for both
passive and active transport.

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In animal cells, an especially important role is played by symports that use the inward flow of Na+ down its
steep electrochemical gradient to drive the import of other solutes into the cell. The epithelial cells that line the
gut, for example, transfer glucose from the gut across the gut epithelium. If these cells had only the passive,
uniport glucose transporters, they would release glucose into the gut after a sugar-free meal as freely as they
take it up from the gut after a sugar-rich meal. But these epithelial cells also possess a glucose–Na+ symport,
which they can use to take up glucose from the gut lumen by active transport, even when the concentration of
glucose is higher inside the cell than in the gut. Because the electrochemical gradient for Na+ is steep, when
Na+ moves into the cell down its gradient, the sugar is, in a sense, “dragged” into the cell with it (Figure 17).
Because the binding of Na+ and glucose is cooperative— the binding of one enhances the binding of the
other—both molecules must be present for coupled transport to occur.

Figure 17. The glucose–na+ symport protein uses the electrochemical na+ gradient to drive the import of glucose.
Glucose can be moved across epithelial cell membranes using both active and passive transporters. Shown here is
one way in which the glucose–Na+ symport protein could actively pump glucose across the membrane using the
influx of Na+ down its electrochemical gradient to drive glucose transport. The pump oscillates randomly between
two alternate states, A and B. In the A state, the protein is open to the extracellular space; in the B state, it is open
to the cytosol. Although Na+ and glucose each bind to the protein in either state, they bind effectively only if both
are present together: the binding of Na+ induces a conformational change in the protein that greatly increases the
protein’s affinity for glucose and vice versa. Because the Na+ concentration is much higher in the extracellular space
than in the cytosol, glucose is more likely to bind to the pump in the a state; therefore, both Na+ and glucose enter
the cell (via an A↔B transition) much more often than they leave it (via a B↔A transition). The overall result is the
net transport of both glucose and Na+ into the cell. Note that, because the binding is cooperative, if one of the two
solutes is missing, the other will fail to bind to the pump, and it will not be transported.

If the gut epithelial cells had only this symport, however, they could never release glucose for use by the other
cells of the body. These cells, therefore, have two types of glucose transporters. In the apical domain of the
plasma membrane, which faces the lumen of the gut, they have the glucose–Na+ symports. These take up
glucose actively, creating a high glucose concentration in the cytosol. In the basal and lateral domains of the
plasma membrane, they have the passive glucose uniports, which release the glucose down its concentration
gradient for use by other tissues (Figure 18). The two types of glucose transporters are kept segregated in their
proper domains of the plasma membrane by a diffusion barrier formed by a tight junction around the apex of
the cell, which prevents mixing of membrane components between the apical and the basal and lateral
domains.

Cells in the lining of the gut and in many other organs, such as the kidney, contain a variety of symports in their
plasma membrane that are similarly driven by the electrochemical gradient of Na+; each of these transporters
specifically imports a small group of related sugars or amino acids into the cell. But Na+-driven antiports are
also important for cell function. For example, the Na+–H+ exchanger in the plasma membranes of many
animal cells uses the downhill influx of Na+ to pump H+ out of the cell and is one of the main devices that
animal cells use to control the pH in their cytosol.

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Figure 18. Two types of glucose transporters enable

gut epithelial cells to transfer glucose across the gut
lining. Glucose is actively transported into the cell by
Na+-driven glucose symports at the apical surface,
and it is released from the cell down its concentration
gradient by passive glucose uniports at the basal and
lateral surfaces. The two types of glucose
transporters are kept segregated in the plasma
membrane by the tight junction. To keep the
concentration of Na+ in the cytosol low, Na+ that
enters the cell via the Na+-driven glucose symport is
pumped out by Na+-K+ pumps. There is ample Na+
in the gut lumen, provided by the diet.

H+ Gradients Are Used to Drive Membrane Transport in Plants, Fungi, and Bacteria

Plant cells, fungi (including yeasts), and bacteria do not have Na+-K+ pumps in their plasma membrane. Instead
of an electrochemical gradient of Na+, they rely mainly on an electrochemical gradient of H+ to drive the transport
of solutes into the cell. The gradient is created by H+ pumps in the plasma membrane, which pump H+ out of
the cell, thus setting up an electrochemical proton gradient, with H+ higher outside than inside; in the process,
the H+ pump also creates an acid pH in the medium surrounding the cell. The uptake of many sugars and amino
acids into bacterial cells, then, is driven by H+ symports, which use the electrochemical gradient of H+ across
the plasma membrane in much the same way that animal cells use the electrochemical gradient of Na+.

In some photosynthetic bacteria, the H+ gradient is created by the activity of light-driven H+ pumps such as
bacteriorhodopsin. In other bacteria, the gradient is created by the activities of plasma membrane proteins that
carry out the final stages of cell respiration that lead to ATP synthesis. But plants, fungi, and many other bacteria
set up their H+ gradient by means of ATPases in their plasma membranes that use the energy of ATP hydrolysis
to pump H+ out of the cell; these ATPases resemble the Na+-K+ pumps and Ca2+ pumps in mammalian cells
discussed earlier.
Figure 19. There are similarities
and differences in transporter-
mediated solute movement in
animal and plant cells. In animal
cells, an electrochemical gradient
of Na+, generated by the Na+-K+
pump (Na+-K+ atpase), is often
used to drive the active transport
of solutes across the plasma
membrane (a). An electrochemical
gradient of h+, usually set up by an
h+ atpase, is often used for this
purpose in plant cells (B), as well
as in bacteria and fungi (not
shown). The lysosomes in animal
cells and the vacuoles in plant and
fungal cells contain an h+ atpase
in their membrane that pumps in
h+, helping to keep the internal
A different type of H+ ATPase is found in the membranes of some intracellular environment of these organelles
acidic. (C) An electron micrograph
organelles, such as the lysosomes of animal cells and the central vacuole of plant shows the vacuole in plant cells in
and fungal cells. Their function is to pump H+ out of the cytosol into the organelle, a young tobacco leaf.
thereby helping to keep the pH of the cytosol neutral and the pH of the interior of
the organelle acidic. Some of the transporters considered in this module are shown in Figure 19 and are listed
Table 2.

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Table 2. Some examples of transporters

We now turn to the transport of ions through channels and discuss how this ion flow can generate a membrane
potential.

ION CHANNELS AND THE MEMBRANE POTENTIAL

In principle, the simplest way to allow a small water-soluble molecule to cross from one side of a membrane to
the other is to create a hydrophilic channel through which the molecule can pass. Channels perform this function
in cell membranes, forming transmembrane aqueous pores that allow the passive movement of small water-
soluble molecules into or out of the cell or organelle.

A few channels form relatively large pores: examples are the proteins that form gap junctions between two
adjacent cells and the porins that form channels in the outer membrane of mitochondria and some bacteria. But
such large, permissive channels would lead to disastrous leaks if they directly connected the cytosol of a cell to
the extracellular space. Thus, most of the channels in the plasma membrane of animal and plant cells have
narrow, highly selective pores. One specialized channel, called aquaporin, facilitates the flow of water across
the plasma membrane. The structure of this protein allows the rapid passage of uncharged water molecules,
while prohibiting the movement of ions, including H+. But the bulk of the cell’s channels enable the transport of
inorganic ions, mainly Na+, K+, Cl–, and Ca2+. It is these ion channels that we discuss next.

Ion Channels Are Ion-selective and Gated

Two important properties distinguish ion channels from simple holes in the membrane. First, they show ion
selectivity, permitting some inorganic ions to pass but not others. Ion selectivity depends on the diameter and
shape of the ion channel and on the distribution of the charged amino acids that line it. An ion channel is narrow
enough in places to force ions into contact with the channel wall so that only those of appropriate size and charge
are able to pass (Figure 20). Narrow channels, for example, will not pass large ions, and channels with a
negatively charged lining will deter negative ions from entering because of the mutual electrostatic repulsion
between like charges. In this way, channels have evolved
that are selective for just one type of ion, such as Cl– or K+.
Each ion in aqueous solution is surrounded by a small shell
of water molecules, and the ions have to shed most of their
associated water molecules in order to pass, in single file,
through the selectivity filter in the narrowest part of the
Figure 20. A K+ channel possesses a selectivity filter that controls
which ion it will transport across the membrane. Shown here is a
portion of a bacterial K+ channel. One of the four protein subunits has
been omitted from the drawing to expose the interior structure of the
pore. From the cytosolic side, the pore opens into a vestibule that sits
in the middle of the membrane. K+ ions in the vestibule are still cloaked
in their associated water molecules (not shown). The narrow selectivity
filter, which links the vestibule with the outside of the cell, is lined with
carbonyl oxygen atoms (red) that bear a partial negative charge and
form transient binding sites for the K+ ions that have shed their watery
shell.
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channel. There, ions make important but very transient contacts with atoms in the amino acids that line the walls
of the selectivity filter (see Figure 20). These precisely positioned atoms allow the channel to discriminate
between ions that differ only minutely in size. This step in the transport process also limits the maximum rate of
passage of ions through the channel. Thus, as ion concentrations are increased, the flow of ions through a
channel at first increases proportionally but then levels off (saturates) at a maximum rate.

The second important distinction between simple pores and ion channels is that ion channels are not
continuously open. Ion transport would be of no value to the cell if there were no means of controlling the flow
and if all of the many thousands of ion channels in a cell membrane were open all of the time. Instead, ion
channels open briefly and then close again (Figure 21). As we discuss later, most ion channels are gated: a
specific stimulus triggers them to switch between a closed and an open state by a change in their conformation.

Figure 21. A typical ion channel fluctuates between closed and open conformations. The channel shown
here in cross section forms a hydrophilic pore across the lipid bilayer only in the ‘open’ conformation. polar
groups line the wall of the pore, while hydrophobic amino acid side chains interact with the lipid bilayer
(not shown). The pore narrows to atomic dimensions in the selectivity filter, where the ion selectivity of the
channel is largely determined

Because an open ion channel does not need to undergo conformational changes with each ion it passes, ion
channels have a large advantage over transporters with respect to their maximum rate of transport. More than
a million ions can pass through an open channel each second, which is a rate 1000 times greater than the
fastest rate of transfer known for any transporter. On the other hand, channels cannot couple the ion flow
to an energy source to carry out active transport. The function of most ion channels is simply to make the
membrane transiently permeable to selected inorganic ions, mainly Na+, K+, Ca2+, or Cl–, allowing these to
diffuse rapidly down their electrochemical gradients across the membrane when the channel gates are open.

Thanks to active transport by pumps and other transporters, most ion concentrations are far from equilibrium
across the membrane. When a channel opens, therefore, ions rush through it. The rush of ions amounts to a
pulse of electric charge delivered either into the cell (as ions flow in) or out of the cell (as ions flow out). The ion
flow changes the voltage across the membrane—the membrane potential—thus altering the electrochemical
driving forces for transmembrane movements of all the other ions. It also forces other ion channels, which are
specifically sensitive to changes in the membrane potential, to open or close in a matter of milliseconds. The
resulting flurry of electrical activity can spread rapidly from one region of the cell membrane to another,
conveying an electrical signal, as we discuss later in the context of nerve cells. This type of electrical signaling
is not restricted to animals; it also occurs in protozoans and plants. Carnivorous plants such as the Venus
flytrap use electrical signaling to sense and trap insects (Figure 22).

Figure 22. A Venus flytrap uses electrical signaling

to capture its prey. The leaves snap shut in less than
half a second when an insect moves on them. The
response is triggered by touching any two of the three
trigger hairs in succession in the center of each leaf.
This mechanical stimulation opens ion channels and
thereby sets off an electrical signal, which, by an
unknown mechanism, leads to a rapid change in
turgor pressure that closes the leaf.

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The membrane potential is the basis of all electrical activity in cells, whether they are plant cells, animal cells,
or protozoans.

Different Types of Stimuli Influence the Opening and Closing of Ion Channels

There are more than a hundred types of ion channels, and even simple organisms can possess many different
channels. The nematode worm C. elegans, for example, has genes that encode 68 different but related K+
channels alone. Ion channels differ from one another primarily with respect to their ion selectivity—the type of
ions they allow to pass; and gating—the conditions that influence their opening and closing. For a voltage-gated
channel, the probability of being open is controlled by the membrane potential (Figure 23A). For a ligand-gated
channel, it is controlled by the binding of some molecule (the ligand) to the channel (Figure 23B and C). For a
stress-gated channel, opening is controlled by a mechanical force applied to the channel (Figure 23D). The
auditory hair cells in the ear are an important example of cells that depend on stress-gated channels. Sound
vibrations pull the channels open, causing ions to flow into the hair cells; this sets up an electrical signal that is
transmitted from the hair cell to the auditory nerve, which conveys the signal to the brain (Figure 12–26).

Figure 23. Gated ion channels respond to different types of stimuli. Depending on the type
of ion channel, the gates open in response to a change in the voltage difference across the
membrane (a), to the binding of a chemical ligand to the extracellular face (B) or the
intracellular face (C) of a channel, or to mechanical stress (D).

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Figure 24. Stress-gated ion channels allow us to hear. (a) A section through the organ of Corti, which runs the length of
the cochlea, the auditory portion of the inner ear. Each auditory hair cell has a tuft of spiky extensions called stereocilia
projecting from its upper surface. The hair cells are embedded in a sheet of supporting cells, which is sandwiched between
the basilar membrane below and the tectorial membrane above. (These are not lipid bilayer membranes but sheets of
extracellular matrix.) (B) Sound vibrations cause the basilar membrane to vibrate up and down, causing the stereocilia to
tilt. Each stereocilium in the staggered array on each hair cell is attached to the next shorter stereocilium by a fine filament.
The tilting stretches the filaments, which pull open stress-gated ion channels in the stereocilium membrane, allowing
positively charged ions to enter from the surrounding fluid. The influx of ions activates the hair cells, which stimulate
underlying endings of the auditory nerve fibers that convey the auditory signal to the brain. The hair-cell mechanism is
astonishingly sensitive: the force required to open a single channel is estimated to be about 2 x 10–13 Newton, and the
faintest sounds we can hear have been estimated to stretch the filaments by an average of about 0.04 nm, which is less
than the diameter of a hydrogen ion.
Voltage-gated Ion Channels Respond to the Membrane Potential

Voltage-gated ion channels play the major role in propagating electrical signals in nerve cells. They are present
in many other cells, too, including muscle cells, egg cells, protozoans, and even plant cells, where they enable
electrical signals to travel from one part of the plant to another, as in the leaf-closing response of the mimosa
tree (Figure 12–27). Voltage-gated ion channels have specialized charged protein domains called voltage
sensors that are extremely sensitive to changes in the membrane potential: changes above a certain threshold
value exert sufficient electrical force on these domains to encourage the channel to switch from its closed to its
open conformation, or vice versa. A change in the membrane potential does not affect how wide the channel is
open but alters the probability that it will be found in its open conformation. Thus, in a large patch of membrane,
containing many molecules of the channel protein, one might find that on average 10% of them are open at any
instant when the membrane is held at one potential, while 90% are open when it is held at another potential.

Figure 25. Voltage-gated ion channels underlie the leaf-closing response in mimosa. (a) Resting leaf. (B
and C) Successive responses to touch. A few seconds after the leaf is touched, the leaflets snap shut. The
response involves the opening of voltage-gated ion channels, generating an electric impulse. When the
impulse reaches specialized hinge cells at the base of each leaflet, a rapid loss of water by these cells
occurs, causing the leaflets to fold closed suddenly and progressively down the leaf stalk.

To appreciate the function of voltage-gated ion channels in a living cell, we have to consider what controls the
membrane potential. The simple answer is that ion channels themselves control it, and the opening and closing
of these channels is what makes it change. This control loop, from ion channels  membrane potential  ion
channels, is fundamental to all electrical signaling in cells. Having seen how the membrane potential can regulate
ion channels, we now discuss how ion channels can control the membrane potential. In the last part of the
module, we consider how this control loop works to propagate signals in nerve cells.

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Membrane Potential Is Governed by Membrane Permeability to Specific Ions

All cells have an electrical potential difference, or membrane potential, across their plasma membrane. To
understand how this potential arises, it is helpful to recall some basic principles of electricity. While electricity in
metals is carried by electrons, electricity in aqueous solutions is carried by ions, which are either positively
(cations) or negatively (anions) charged. An ion flow across a cell membrane is detectable as an electric current,
and an accumulation of ions, if not exactly balanced by an accumulation of oppositely charged ions, is detectable
as an accumulation of electric charge, or a membrane potential (Figure 26).

To see how the membrane potential is generated and maintained, consider the ion movements into and out of a
typical animal cell in an unstimulated ‘resting’ state. The negative charges on the organic molecules confined
within the cell are largely balanced by K+, the predominant positive ion inside the cell. The high intracellular
concentration of K+ is in part generated by the Na+-K+ pump, which actively pumps K+ into the cell. This leads
to a large concentration difference for K+ across the plasma membrane, with the concentration of K+ being much
higher inside the cell than outside. The plasma membrane, however, also contains a set of K+ channels known
as K+ leak channels. These channels randomly flicker between open and closed states no matter what the
conditions are inside or outside the cell, and when they are open, they allow K+ to move freely. In a resting cell,
these are the main ion channels open in the plasma membrane, thus making the resting plasma membrane
much more permeable to K+ than to other ions.

Figure 26. The distribution of ions on either side of the lipid bilayer gives rise to the
membrane potential. The membrane potential results from a thin (<1 nm) layer of ions close
to the membrane, held in place by their electrical attraction to oppositely charged counterparts
on the other side of the membrane. (a) When there is an exact balance of charges on either
side of the membrane, there is no membrane potential. (B) When ions of one type cross the
membrane, they set up a charge difference between the two sides of the membrane that
creates a membrane potential. The number of ions that must move across the membrane to
set up a membrane potential is a tiny fraction of those present. (6000 K+ ions crossing 1 mm2
of cell membrane are enough to shift the membrane potential by about 100 mV; the number
of K+ ions in 1 mm3 of bulk cytoplasm is 70,000 times larger than this.)

K+ therefore has a tendency to flow out of the cell through these channels down its steep concentration gradient.
But any transfer of positive charge to the exterior leaves behind unbalanced negative charge within the cell,
thereby creating an electrical field, or membrane potential, which will oppose any further movement of K+ out of
the cell. Within a millisecond or so, an equilibrium condition is established in which the membrane potential is
just strong enough to counterbalance the tendency of K+ to move out down its concentration gradient—that is,
in which the electrochemical gradient for K+ is zero, even though there is still a much higher concentration of K+
inside the cell than out (Figure 27).

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Figure 27. K+ leak channels play a

major role in generating the membrane
potential across the plasma membrane.
(a) A hypothetical situation where the K+
leak channel is closed and the
membrane potential is zero. (B) As soon
as the channel opens, K+ will tend to
leave the cell, moving down its
concentration gradient. Assuming the
membrane contains no open channels
permeable to other ions, K+ ions will
cross the membrane, but negative ions
will be unable to follow them. The result
will be an excess of positive charge on
the outside of the membrane and of
negative charge on the inside. This gives
rise to a membrane potential that tends
to drive K+ back in. at equilibrium, the
effect of the K+ concentration gradient is
exactly balanced by the effect of the
membrane potential, and there is no net
movement of K+.

The resting membrane potential is the membrane potential in such steady-state conditions, in which the flow of
positive and negative ions across the plasma membrane is precisely balanced, so that no further difference in
charge accumulates across the membrane. The membrane potential is measured as a voltage difference across
the membrane. In animal cells, the resting membrane potential varies between –20 and –200 millivolts (mV),
depending on the organism and cell type. It is expressed as a negative value because the interior of the cell is
negative with respect to the exterior, as the negative charges inside the cell are in slight excess over positive
charges. The actual value of the resting membrane potential in animal cells is chiefly a reflection of the K+
concentration gradient across the plasma membrane, because, at rest, this membrane is chiefly permeable to
K+, and K+ is the main positive ion inside the cell.

Suppose now that other channels permeable to some other ion—say, Na+—are suddenly opened in the plasma
membrane. Because Na+ is at a higher concentration outside the cell than inside, Na+ will move into the cell
through these channels and the membrane potential will become less negative, maybe even reversing sign to
become positive (so that the interior of the cell is positive with respect to the exterior). The membrane potential
will shift toward a new value that is a compromise between the negative value that would correspond to
equilibrium for K+ and the positive value that would correspond to equilibrium for Na+. Any change in the
membrane’s permeability to specific ions—that is, any change in the numbers of ion channels of different sorts
that are open—thus causes a change in the membrane potential. The membrane potential, therefore, is
determined by both the state of the ion channels in the membrane and the ion concentrations in the cytosol and
extracellular medium. Because the electrical processes at the plasma membrane occur very quickly compared
with changes in the bulk ion concentrations, over the short term—milliseconds as compared with seconds or
minutes—it is the ion channels that are most important in controlling the membrane potential.

To see how the interplay between the membrane potential and ion channels is used for electrical signaling, we
now turn from the behavior of ions and ion channels to the behavior of entire cells. We take nerve cells as our
prime example, for they, more than any other cell type, have made a profession of electrical signaling and employ
ion channels in the most sophisticated ways.

ION CHANNELS AND SIGNALING IN NERVE CELLS

The fundamental task of a nerve cell, or neuron, is to receive, conduct, and transmit signals. Neurons carry
signals inward from sense organs to the central nervous system—the brain and spinal cord. In the central
nervous system, neurons signal from one to another through networks of enormous complexity, allowing the
brain and spinal cord to analyze, interpret, and respond to the signals coming in from the sense organs. From
the central nervous system, neurons extend processes outward to convey signals for action to muscles and

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glands. To perform these functions, neurons are often extremely elongated: the motor neurons in a human that
carry signals from the spinal cord to a muscle in the foot, for example, may be a meter long.

Every neuron consists of a cell body (containing the nucleus) that has a number of long, thin extensions
radiating outward from it. Usually, a neuron has one long axon, which conducts signals away from the cell body
toward distant target cells; it also usually has several shorter, branching dendrites, which extend from the cell
body like antennae and provide an enlarged surface area to receive signals from the axons of other neurons
(Figure 28). The axon commonly divides at its far end into many branches, each of which ends in a nerve terminal,
so that the neuron’s message can be passed simultaneously to many target cells—either other neurons or
muscle or gland cells. Likewise, the branching of the dendrites can be extensive, in some cases sufficient to
receive as many as 100,000 inputs on a single neuron.

No matter what the meaning of the signal a neuron carries—whether it is visual information from the eye, a motor
command to a muscle, or one step in a complex network of neural processing in the brain—the form
of the signal is always the same: it consists of changes in the electrical potential across the neuron’s plasma
membrane.

Figure 28. A typical neuron has a cell body, a

single axon, and multiple dendrites. The axon
conducts signals away from the cell body toward
its target cells, while the multiple dendrites
receive signals from the axons of other neurons.
The red arrows indicate the direction in which
signals are conveyed.

Action Potentials Provide for Rapid Long-Distance Communication

A neuron is stimulated by a signal—typically from another neuron—delivered to a localized site on its surface.
This signal initiates a change in the membrane potential at that site. To transmit the signal onward, however, the
change in membrane potential has to spread from this point, which is usually on a dendrite or the cell body, to
the axon terminals, which relay the signal to the next cells in the pathway. Although a local change in membrane
potential will spread passively along an axon or a dendrite to adjacent regions of the plasma membrane, it rapidly
becomes weaker with increasing distance from the source. Over short distances, this weakening is unimportant.
But for long-distance communication, such passive spread is inadequate. In the same way, a telephone signal
can be transmitted without amplification the short distances through the wires in your home town, but for
transmission across an ocean by an undersea cable, the strength of the signal has to be boosted at intervals.

Neurons solve this long-distance communication problem by employing an active signaling mechanism: a local
electrical stimulus of sufficient strength triggers an explosion of electrical activity in the plasma membrane that
is propagated rapidly along the membrane of the axon and sustained by automatic renewal all along the way.
This traveling wave of electrical excitation, known as an action potential, or a nerve impulse, can carry a
message, without the signal weakening, from one end of a neuron to the other at speeds of up to 100 meters
per second.

Action Potentials Are Usually Mediated by Voltage-gated Na+ Channels

An action potential in a neuron is typically triggered by a sudden local depolarization of the plasma membrane—
that is, by a shift in the membrane potential to a less negative value (that is, a shift towards zero). We discuss
later how such a depolarization is caused by the action of signal molecules—neurotransmitters—released by
another neuron. A stimulus that causes a sufficiently large depolarization to pass a certain threshold value,
promptly causes voltage-gated Na+ channels to open temporarily at that site, allowing a small amount of Na+ to
enter the cell down its electrochemical gradient. The influx of positive charge depolarizes the membrane further
(that is, it makes the membrane potential even less negative), thereby opening more voltage-gated Na+
channels, which admit more Na+ ions and cause still further depolarization. This process continues in a self-
amplifying fashion until, within about a millisecond, the membrane potential in the local region of membrane has
shifted from its resting value of about –60 mV to about +40 mV (Figure 29). This voltage is close to the membrane
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potential at which the electrochemical driving force for movement of Na+ across the membrane is zero—that is,
at which the effects of the membrane potential and the concentration gradient for Na+ are equal and opposite
and Na+ has no further tendency to enter or leave the cell. If the channels continued to respond indefinitely in
this way to the altered membrane potential, the cell would get stuck at this point with all of its voltage-gated Na+
channels predominantly open.

Figure 29. An action potential is triggered by a rapid

change in membrane potential. The resting
membrane potential in this neuron is –60 mV. The
action potential is triggered when a stimulus
depolarizes the plasma membrane by about 20 mV,
making the membrane potential –40 mV, which is
the threshold value in this cell for initiating an action
potential. Once an action potential is triggered, the
membrane rapidly depolarizes further: the
membrane potential (red curve) swings past zero
and reaches +40 mV before it returns to its resting
negative value, as the action potential terminates.
The green curve shows how the membrane
potential would simply have relaxed back to the
resting value after the initial depolarizing stimulus if
there had been no voltage-gated ion channels in the
plasma membrane.

The cell is saved from this fate because the Na+ channels have an automatic inactivating mechanism, which
causes them to rapidly adopt (within a millisecond or so) a special inactive conformation, where the channel is
unable to open again. Even though the membrane is still depolarized, the Na+ channels will remain in this
inactivated state until a few milliseconds after the membrane potential returns to its initial negative value. A
schematic illustration of these three distinct states of the voltage-gated Na+ channel—closed, open, and
inactivated—is shown in Figure 30. How they contribute to the rise and fall of the action potential is shown in
Figure 12–35

Figure 30. A voltage-gated Na+ channel can

adopt at least three conformations. The
channel can flip from one conformation to
another, depending on the membrane
potential. When the membrane is at rest
(highly polarized), the closed conformation is
the most stable. When the membrane is
depolarized, however, the open conformation
is more stable, and so the channel has a high
probability of opening; but in the depolarized
membrane the inactivated conformation is
more stable still, and so, after a brief period
spent in the open conformation, the channel
becomes inactivated and cannot open. The
red arrows indicate the sequence that follows
a sudden depolarization, and the black arrow
indicates the return to the original
conformation after the membrane is
repolarized.

The membrane is further helped to return to its resting value by the opening of voltage-gated K+ channels. These
also open in response to depolarization of the membrane, but not as promptly as the Na+ channels, and they
then stay open as long as the membrane remains depolarized. As the action potential reaches its peak, K+ ions
(carrying positive charge) therefore start to flow out of the cell through these K+ channels down their
electrochemical gradient, temporarily unhindered by the negative membrane potential that restrains them in the
resting cell. The rapid outflow of K+ through the voltage-gated K+ channels brings the membrane back to its
resting state more quickly than could be achieved by K+ outflow through the K+ leak channels alone.

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Figure 31. Ion flows dictate the rise and fall of an action
potential. In this example, the action potential is triggered
by a brief pulse of electric current (a), which partially
depolarizes the membrane, as shown in the plot of
membrane potential versus time (B). (B) Shows the
course of the action potential (red curve) that is caused
by the opening and subsequent inactivation of voltage-
gated Na+ channels, whose state is shown in (C). Even if
re-stimulated, the membrane cannot produce a second
action potential until the Na+ channels have returned from
the inactivated to the simply closed conformation until
then, the membrane is resistant, or refractory, to
stimulation

This description of an action potential concerns only a small patch of plasma membrane. The self-amplifying
depolarization of the patch, however, is sufficient to depolarize neighboring regions of membrane, which then go
through the same self-amplifying cycle. In this way, the action potential spreads outward as a traveling wave
from the initial site of depolarization, eventually reaching the extremities of the axon (Figure 32). Faced with the
consequences of the Na+ and K+ fluxes caused by a passing action potential, local Na+/K+ ATPase molecules
labor continuously to restore the ion gradients across the plasma membrane of the axon.

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Figure 32. An action potential can be propagated along the

length of an axon. (a) This schematic figure shows the voltages
(V1, V2, and V3) that would be recorded from a set of
intracellular electrodes placed at intervals along the axon, whose
width is greatly exaggerated here. Note that the action potential
does not weaken as it travels. The activating stimulus is
administered at time t = 0, and the direction in which the action
potential is traveling is indicated by the red arrow. (B) The
changes in the Na+ channels and the consequent flows of
electric current across the membrane (orange arrows) disturbs
the membrane potential and gives rise to the traveling action
potential, as shown here. The region of the axon with a
depolarized membrane is shaded in blue. Note that an action
potential can only travel forward from the site of depolarization.
This is because Na+-channel inactivation prevents the
depolarization from spreading backward

Voltage-gated Ca2+ Channels Convert Electrical Signals into Chemical Signals at Nerve Terminals

When an action potential reaches the nerve terminals at the end of an axon, the signal must somehow be relayed
to the target cells that the nerve terminals contact: usually neurons or muscle cells. The signal is transmitted to
the target cells at specialized junctions known as synapses. At most synapses, the plasma membranes of the
transmitting and receiving cells—the presynaptic and the postsynaptic cells, respectively— are separated from
each other by a narrow synaptic cleft (typically 20 nm across), which the electrical signal cannot cross (Figure
12–40). For the message to be transmitted from one neuron to another, the electrical signal is converted into a
chemical signal, in the form of a small signal molecule known as a neurotransmitter.

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Figure 33. Neurons transmit chemical signals across synapses. an electron micrograph (a) and drawing (B) of a
cross section of two nerve terminals (yellow) forming synapses on a single nerve cell dendrite (blue) in the
mammalian brain. Note that both the presynaptic and postsynaptic membranes are thickened at the synapse.

Neurotransmitters are stored ready-made in the nerve terminals, packaged in membrane-enclosed synaptic
vesicles (see Figure 33). When the action potential reaches the terminal, the neurotransmitters are released
from the nerve ending by exocytosis. This link between the action potential and secretion involves the activation
of yet another type of voltage-gated cation channel. The depolarization of the nerve-terminal plasma membrane
caused by the arrival of the action potential transiently opens voltage-gated Ca2+ channels, which are
concentrated in the plasma membrane of the presynaptic nerve terminal. Because the Ca2+ concentration
outside the cell is more than 1000 times greater than the free Ca2+ concentration in the cytosol, Ca2+ rushes
into the nerve terminal through the open channels. The resulting increase in Ca2+ concentration in the cytosol
of the presynaptic cell triggers the fusion of some of the synaptic vesicles with the plasma membrane, releasing
the neurotransmitter into the synaptic cleft. Thanks to the voltage-gated Ca2+ channels, the electrical signal has
now been converted into a chemical signal (Figure 34).

Figure 34. An electrical signal is converted into a

chemical signal at a nerve terminal. When an action
potential reaches a nerve terminal, it opens voltage-
gated Ca2+ channels in the plasma membrane,
allowing Ca2+ to flow into the terminal. The increased
Ca2+ in the nerve terminal stimulates the synaptic
vesicles to fuse with the plasma membrane, releasing
their neurotransmitter into the synaptic cleft.

Transmitter-gated Channels in Target Cells Convert Chemical Signals Back into Electrical Signals

The released neurotransmitter rapidly diffuses across the synaptic cleft and binds to neurotransmitter receptors
concentrated in the postsynaptic membrane of the target cell. The binding of neurotransmitter to its receptors
causes a change in the membrane potential of the target cell, which can trigger the cell to fire an action potential.
The neurotransmitter is then quickly removed from the synaptic cleft—either by enzymes that destroy it, or by
reuptake into the nerve terminals that released it or into neighboring cells. This rapid removal of the
neurotransmitter limits the signal and ensures that, when the presynaptic cell falls quiet, the postsynaptic cell will
fall quiet as well.

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Neurotransmitter receptors can be of various types; some mediate relatively slow effects in the target cell,
whereas others trigger more rapid responses. Rapid responses—on a time scale of milliseconds—depend on
receptors that are transmitter-gated ion channels (also called ion-channel- coupled receptors). These constitute
a subclass of ligand-gated ion channels, and their function is to convert the chemical signal carried by a
neurotransmitter back into an electrical signal. The channels open transiently in response to the binding of the
neurotransmitter, thus changing the ion permeability of the postsynaptic membrane. This in turn causes a change
in the membrane potential (Figure 35); if the change is big enough, it can trigger an action potential in the
postsynaptic cell. A well-studied example of a transmitter-gated ion channel is found at the neuromuscular
junction—the specialized type of synapse formed between a neuron and a muscle cell. In vertebrates, the
neurotransmitter here is acetylcholine, and the transmitter-gated ion channel is the acetylcholine receptor (Figure
36).

Figure 35. A chemical signal is converted into an

electrical signal by transmitter-gated ion channels at
a synapse. The released neurotransmitter binds to
and opens the transmitter-gated ion channels in the
plasma membrane of the postsynaptic cell. The
resulting ion flows alter the membrane potential of the
postsynaptic cell, thereby converting the chemical
signal back into an electrical one

Figure 36. The acetylcholine receptor, present in the plasma membrane of muscle cells, opens when it
binds to the neurotransmitter acetylcholine released by a nerve. (a) This transmitter-gated ion channel is
composed of five transmembrane protein subunits that combine to form an aqueous pore across the lipid
bilayer. The pore is lined by five transmembrane a helices, one contributed by each subunit. (B)
Negatively charged amino acid side chains at either end of the pore (indicated here by red minus signs)
ensure that only positively charged ions, mainly Na+ and K+, can pass. The blue subunit has been
removed here to show the interior of the pore. When the channel is in its closed conformation, the pore
is occluded (blocked) by hydrophobic amino acid side chains in the region called the gate. (C) When
acetylcholine binds, the channel undergoes a conformational change in which these side chains move
apart and the gate opens, allowing Na+ to flow across the membrane down its electrochemical gradient.
K+ (not shown here) will flow in the opposite direction down its electrochemical gradient. Even with
acetylcholine bound, the channel flickers randomly between the open and closed states.

Neurons Receive Both Excitatory and Inhibitory Inputs

The response produced by a neurotransmitter at a synapse can be either excitatory or inhibitory. Excitatory
neurotransmitters (delivered by axon terminals of excitatory neurons) stimulate the postsynaptic cell,
encouraging it to fire an action potential. Inhibitory neurotransmitters (delivered by axon terminals of inhibitory
neurons) do the opposite, discouraging the postsynaptic cell from firing. The drug curare, which South American

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Indians used to make poison arrows and surgeons use to relax muscles during an operation, causes paralysis
by blocking the delivery of excitatory signals at neuromuscular junctions. By contrast, strychnine, a common
ingredient in rat poisons, causes muscle spasms, convulsions, and death by blocking the delivery of inhibitory
signals.

Excitatory and inhibitory neurotransmitters bind to different receptors, and it is the character of the receptor that
makes the difference between excitation and inhibition. The chief receptors for excitatory neurotransmitters,
mainly acetylcholine and glutamate, are ligand-gated cation channels. When the neurotransmitter binds, the
channels open to allow an influx of cations, which depolarizes the plasma membrane toward the threshold
potential required for triggering an action potential. Stimulation of these receptors thus tends to activate the
postsynaptic cell. The receptors for inhibitory neurotransmitters, mainly Ɣ-aminobutyric acid (GABA) and glycine,
by contrast, are ligand-gated Cl– channels. When the neurotransmitter binds, the channels open, but very little
Cl– enters the cell at this point because the driving force for movement of Cl– across the membrane is close to
zero at the resting membrane potential. If an excitatory neurotransmitter opens Na+ channels at the same time,
however, the resulting depolarization caused by the Na+ influx will cause Cl– to move into the cell through the
open Cl– channels, neutralizing the effect of the Na+ influx (Figure 37). In this way, inhibitory neurotransmitters
suppress the production of an action potential by making the target cell membrane much harder to depolarize.

Figure 37. Synapses can be excitatory or

inhibitory. Excitatory neurotransmitters
activate ion channels that allow the passage
of Na+ and Ca2+, whereas inhibitory
neurotransmitters activate ion channels that
allow the passage of Cl–.

The locations and functions of these ion channels, and of some of the other ion channels discussed in this
module, are summarized in Table 3.

Table 3. Some examples of ion channels

Transmitter-gated Ion Channels Are Major Targets for Psychoactive Drugs

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Most drugs used in the treatment of insomnia, anxiety, depression, and schizophrenia exert their effects at
synapses in the brain, and many of them act by binding to transmitter-gated ion channels. The barbiturates and
tranquilizers such as Valium, Ambien, and temazepam, for example, bind to GABA-gated Cl– channels. Their
binding makes the channels easier to open by GABA, thus making the cell more sensitive to GABA’s inhibitory
action. By contrast, the antidepressant Prozac blocks the reuptake of an excitatory neurotransmitter, serotonin,
increasing the amount of serotonin available at those synapses that use this transmitter. Why this should relieve
depression is still a mystery.

The number of distinct types of neurotransmitter receptors is very large, although they fall into a small number
of families. There are, for example, many subtypes of acetylcholine, glutamate, GABA, glycine, and serotonin
receptors; they are usually located in different neurons and often differ only subtly in their properties. With such
a large variety of receptors, it may be possible to design a new generation of psychoactive drugs that will act
more selectively on specific sets of neurons to alleviate the mental illnesses that devastate so many people’s
lives. One percent of the human population, for example, have schizophrenia, another 1% have bipolar disorder,
and many more suffer from anxiety or depression.

Synaptic Connections Enable you to Think, Act, and Remember

At a synapse, the nerve terminal of the presynaptic cell converts an electrical signal into a chemical one, and the
postsynaptic cell converts the chemical signal back into an electrical one. Interference with these processes, for
good or ill, is of enormous practical importance to us. But why has evolution favored such an apparently inefficient
way to pass on an electrical signal? It would seem more efficient to have a direct electrical connection between
the pre- and postsynaptic cells, or to do away with the synapse altogether and use a single continuous cell.

The value of synapses that can handle chemical signals becomes clear when we consider how they function in
the context of the nervous system— a huge network of neurons, interconnected by many branching pathways,
performing complex computations, storing memories, and generating plans for action. To carry out these
functions, neurons have to do more than merely generate and relay signals: they must also combine them,
interpret them, and record them. Chemical synapses make these activities possible. A motor neuron in the spinal
cord, for example, receives inputs from hundreds or thousands of other neurons that make synapses on it (Figure
38). Some of these signals tend to stimulate the neuron, while others tend to inhibit it. The motor neuron has to
combine all of the information it receives and react either by firing action potentials along its axon to stimulate a
muscle or by remaining quiet. This task of computing an appropriate output from a cacophonous babble of inputs
is achieved by a complicated interplay between different types of ion channels in the neuron’s plasma membrane.
Each of the hundreds of types of neurons in your brain has its own characteristic set of receptors and ion
channels that enables the cell to respond in a particular way to a certain set of inputs and thus to perform its
specialized task. Furthermore, the ion channels and other components at a synapse can also undergo lasting
modifications according to the usage they have experienced, thereby preserving traces of past events. In this
way, memories are stored. Ion channels, therefore, are at the heart of the machinery that enables you to act,
think, feel, speak.

Figure 38. Thousands of synapses form on the

cell body and dendrites of a motor neuron in the
spinal cord. (a) Many thousands of nerve terminals
synapse on the neuron, delivering signals from
other parts of the animal to control the firing of
action potentials along the neuron’s axon. (B) A rat
nerve cell in culture. Its cell body and dendrites
(green) are stained with a fluorescent antibody that
recognizes a cytoskeletal protein. Thousands of
axon terminals (red) from other nerve cells (not
visible) make synapses on the cell’s surface; they
are stained with a fluorescent antibody that
recognizes a protein in synaptic vesicles. Electrical
signals are sent out along axons, relayed across
synapses, and passed in along dendrites toward
the nerve cell body. The signaling depends on
movements of ions across the plasma membranes
of the nerve cells

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