A LIVING CELL is like an ancient walled city buzzing with activity. It has
its workshops, storehouses, administrative centre and streets teeming with
traffic, but most importantly of all it is surrounded by a wall that encloses
and defines it. This wall—the plasma membrane—is responsible
for protecting the cell from its hazardous surroundings. Whereas walls were
built to protect cities from armed invaders, the plasma membrane evolved to
protect the cell from substances in its immediate environment such as toxic
acids, alkalis and ions. The evolution of an enclosing membrane was fundamental
to the development of primitive life, just as the growth of the first cities was
a milestone in human history. It provided a “reaction flask” in which to control
and experiment with the chemicals of life in relatively stable conditions. And
it allowed cells to maintain an internal environment that is ideal for keeping
proteins stable and functioning.
Ever since, the membrane has prevented the escape of valuable products such
as proteins, nucleic acids and carbohydrates. But, like a city wall, it allows
vital nutrients to pass inside through tightly guarded “gates” and waste
products to be expelled, and as the only point of contact with the outside
world, it can receive and transmit messages. In fact, by facilitating
communication, the plasma membrane is the basis for all multicellular
organisation—allowing cells to cooperate in the building and maintenance
of tissues and organs.
Just as the buildings within a city are protected by their own walls,
discrete structures which perform particular functions within a cell—its
´Ç°ů˛µ˛ą˛Ô±đ±ô±ô±đ˛ő—are also surrounded by membranes with the same
underlying structure as the plasma membrane. They are all composed of two sheets
of phospholipid molecules arranged back-to-back
(see Figure 2). Most
phospholipids have two tails that are hydrophobic—o°ů
“water-hating”—and a head that is hydrophilic—â¶Äťw˛ąłŮ±đ°ů-±ô´Ç±ąľ±˛Ô˛µâ€ť
(see Figure 3).
All the phospholipids in each sheet are aligned in the same
direction, with their water-repellent tails weakly bonded to those of the other
sheet to form a “lipid bilayer” about 5 millionths of a millimetre
(5 nanometres) thick. In total, there are about a billion lipid molecules in the
plasma membrane of a small animal cell, such as a red blood cell.
Advertisement
One of the remarkable things about the bilayer is that lipids are free to
move rapidly in the plane of their own layer, making the structure a liquid
crystal—neither solid nor liquid. This gives the membrane structural
integrity but, at the same time great flexibility, allowing the cell to change
its shape, expand and contract. The unique structure also allows the membrane to
break and reassemble itself, which is vital during cell division and for forming
small membrane-bound sacs called vesicles for importing and exporting
large particles. To give some idea of the fluid nature of the plasma membrane, a
single lipid molecule in a large bacterium can travel the entire length of the
cell—about 3.5 thousandths of a millimetre for Escherichia coli
—in a second.
Plasma membranes contain two other types of lipid: cholesterol and
glycolipids. Cholesterol is an important constituent of all animal
membranes as it prevents strong bonds forming between the lipid tails and so
keeps the structure fluid. Glycolipids are mostly found in the outer
“leaflet” of the bilayer, where they likely have a role in electrical insulation
and inter-cell contact and recognition.
The membrane is studded with proteins, some of which are free-floating,
others anchored to the cell’s internal scaffolding, the cytoskeleton (see
Inside Science No. 95). Proteins account for about 50 per cent of the membrane’s
mass, but there are around 50 lipid molecules for every protein molecule: the
proteins are around 50 times bigger. The proteins act as receptors for
transmitting information across the membrane, by binding to specific molecules
in the environment and translating their signal into chemical messages inside
the cell. They also act as channels and carriers allowing molecules in and
out.
Membrane proteins come in two broad structural types. So-called
transmembrane proteins extend from one side of the bilayer to the other.
They achieve this feat by being amphiphilic—in common with
phospholipids, they have both hydrophilic and hydrophobic parts. Their
hydrophilic regions are exposed to water on either side of the bilayer, and
their hydrophobic regions weakly bond with the tails of phospholipid molecules
inside the bilayer. Often, they have regions of positive charge adjacent to the
inner face of the membrane that firmly anchor them to the negatively charged
phospholipid heads. Transmembrane proteins tend to be involved in ferrying
substances across the membrane, or in mechanically linking the cytoskeleton to
structures outside the cell, such as other cells or the mesh of fibrous proteins
surrounding them.
Modes of Transport
Carriers and Channels
By contrast, other proteins sit on the external or internal surface of the
membrane, and these are often involved in cell signalling. They receive
and transmit messages by binding to signalling molecules—a bit like
throwing a switch controlling the chemical machinery of the cell or its
neighbours.
What makes the plasma membrane so effective as a protective barrier in a
watery environment is its hydrophobic interior. This allows the cell to maintain
different concentrations of aqueous solutes inside and outside, and the same
holds for membrane-bound organelles, such as mitochondria. Ions such as
chloride, sodium and potassium are unable to cross the bilayer unaided. Small
polar molecules—molecules with an uneven distribution of
charge—have some difficulty crossing it. But large polar molecules, such
as sugars, amino acids and nucleotides, are incapable of breaching the closely
knit, hydrophobic meshwork of the membrane interior. Water molecules on the
other hand, despite being polar, are small enough to squeeze through.
In order to ingest nutrients, excrete waste products and regulate the
concentrations of ions in their interiors, cells have evolved ways to usher
selected substances across their membranes. Specialised transmembrane proteins
transport ions and other water-soluble molecules. The importance of these
proteins is testified by the discovery that almost one in five genes identified
so far in E. colicodes for a protein involved in membrane transport.
Each protein transports a particular kind of molecule. This was demonstrated in
the 1950s, when biologists found that knocking out single genes in bacteria
prevented them from transporting specific sugar molecules. In humans, several
inherited diseases are caused by the inability of cell membranes to transport a
specific molecule. Cystic fibrosis, the most common inherited disease in the
developed world, is caused by a faulty membrane protein for transporting
chloride ions and affects the cells of glands such as those that secrete mucus.
As a result, extra-thick mucus is secreted that gums up intestinal glands, the
pancreas and bronchi of the lungs.
There are two main classes of protein involved in transport: carrier
proteins and channel proteins. The precise mechanism of transport
remains unclear, but carriers are believed to bind to specific molecules on one
side of the membrane, then transfer them across the bilayer by a series of
reversible contortions, finally releasing them on the other side. They can be
thought of as membrane-bound enzymes and the solutes they transport as their
substrates (see Figure 4).
By contrast, channel proteins form narrow hydrophilic pores through which
small ions can rapidly diffuse from a high concentration on one side of
the membrane to a lower concentration on the other. Diffusion is a passive
process, so the cell doesn’t expend any energy when ions pass through its
channels. But only ions of a specific size and charge can negotiate a particular
type of channel. Like enzymes, these proteins have binding sites for specific
ions, making them highly selective. In addition, channels may open and close
spontaneously, or they can be gated—meaning they will only open up
under particular circumstances. Voltage-gated channels only open when a
threshold potential difference across the membrane is reached; mechanically
gated channels open in response to mechanical stress; and ligand-gated channels
only open in the presence of particular ligands—molecules that bind
to proteins, for example an ion or nucleotide inside the cell, or a signalling
molecule outside, such as the neurotransmitter acetylcholine.
More than a million ions can diffuse through a single channel in a
second—about a thousand times faster than transport by carrier protein.
Combined with their hair-trigger responses to mechanical stress, ligands or
changes in voltage, this extraordinary speed makes ion channels perfect for
rapid reactions. Cells can build up large ion concentration differences across
their membranes, effectively storing up potential energy like water building up
behind a hydroelectric dam. This energy can be released in an instant when the
ion channel floodgates open. The leaf-closing response of a mimosa plant is
brought about by the sudden opening of ion channels, as is the ability of the
single-celled Paramecium to change direction when it collides with an
object. And every time you move a muscle you have ion channels in your motor
nerves and muscle fibres to thank (see Inside Science No. 47).
Whereas channel proteins merely facilitate diffusion, some carriers are
coupled to a source of energy and actively pump solutes across the
membrane—analogous to pumping water uphill. This “active transport” allows
solutes to be moved against their electrochemical gradients. For example, ion
pumps may move positively charged ions from an area where their concentration is
low to an area where it is high, perhaps even from an area of overall negative
charge to an area with net positive charge. They perform this trick either by
splitting molecules of ATP, which is the cell’s chemical fuel, or by
harnessing the potential energy stored in the electrochemical gradient of
another solute. Two of the best-known and most widespread ion pumps are the
sodium-potassium pump, which plays a critical role in nearly all animal
plasma membranes by helping cells maintain their volume, and the calcium
pump which, among many other things, helps to regulate the contraction of muscle
fibres.
A typical animal cell invests a hefty one-third of all its energy resources
into fuelling its sodium-potassium pumps. In animal cells, the concentration of
potassium ions (K+) is kept between 10 and 30 times as high inside the cell as
outside. The reverse is true of sodium ions (Na+), and cells use this Na+
concentration gradient to regulate their volume through osmosis. They also use
it to drive the transport of sugars and amino acids into the cell. The Na+/K+
pump maintains these vital ion gradients by splitting ATP, and for every ATP
molecule it splits the pump, expels three Na+ ions from the cell and admits two
K+ ions. Like all carrier proteins, the pump can be thought of as a
membrane-bound enzyme, and since part of its job involves splitting ATP, it is
referred to as an ATPase. Other membrane-bound ATPases function as calcium and
hydrogen pumps (see “Drugs for combating peptic ulcers”).
Small, water-soluble organic molecules can also be shuttled across the
membrane by specialised channel proteins called transporters. Some merely
facilitate diffusion “downhill” from an area of high solute concentration to an
area of lower concentration—known as passive transport—błÜłŮ
others can actually pull solutes up their electrochemical gradient by using
potential energy stored in another ion gradient. This is called secondary
active transport, because it relies on ion pumps such as that described
above to maintain the gradient.
A good example of the interplay between ion pumps and transporters can be
seen in cells in the epithelial lining of the intestine. These cells perform the
vital task of absorbing glucose from the gut on one of their faces and
transferring it to the extracellular fluid on the other side—from where it
passes into the bloodstream. On the side exposed to the gut’s contents, glucose
is carried across the membrane from a low concentration to a higher
concentration by secondary active transport. In effect, glucose carriers use the
passive diffusion of sodium from the gut into the cell to drive the transport of
glucose. Meanwhile, on the other side of the cell, Na+/K+ ATPase pumps
actively expel sodium from the cell to maintain this diffusion gradient. And as
the concentration of glucose inside the cell rises, another kind of glucose
carrier facilitates its diffusion into the extracellular fluid, and so into the
bloodstream.
Even though biologists remain unsure precisely how carriers such as glucose
transporters do their job, their handiwork is of enormous interest to drug
designers (see Inside Science No. 65). For example, it was recently found that a
type of drug given to AIDS patients to stop HIV from replicating may have the
unfortunate habit of blocking glucose transporters. The knock-on effect of this
appears to be that patients taking these drugs, known as protease
inhibitors, develop diabetes and have an unsightly redistribution of fatty
tissue beneath their skin. Now that pharmacologists have some inkling about what
causes these side-effects, they may be able to design drugs that are free of
them.
Some molecules, such as proteins and nucleic acids, are too large to cross
the membrane by any of the means described above. Instead, the membrane as a
whole either allows part of the external medium to be brought into the cell,
along with the molecules the cell needs (endocytosis), or part of the
cytoplasm to be externalised (exocytosis). During endocytosis, the plasma
membrane surrounds a portion of the external medium, rather like an amoeba
engulfing its prey. The flexible membrane invaginates to form a hollow,
then an almost-complete sphere. Finally, the membrane fuses and breaks to create
a membrane-bound vesicle, which is drawn into the cell. Endocytosis may be
triggered when a specific molecule, such as LDL cholesterol (the “bad” form of
cholesterol), binds to a receptor on the outer surface of the plasma
membrane.
Products earmarked for export from the cell, on the other hand, are packaged
in vesicles which fuse with the plasma membrane, voiding their contents to the
outside. This is how neurotransmitters such as serotonin—a brain
chemical which helps to determine our mood—are released at the synapses
which form the junctions between nerves.
Indeed, proteins called receptors that are embedded in the plasma
membrane allow the activity of the billions of cells in a multicellular organism
to be coordinated at every level. At the highest level, synaptic receptors for
neurotransmitters such as serotonin and acetylcholine receive the long-distance
messages being relayed through the nervous system. Hormone receptors perform an
analogous role in the endocrine system, and receptors on the surface of
lymphocytes and other immune cells mediate immune responses to invading
organisms. But at the most fundamental level, receptors allow groups of
specialised cells to cooperate with their neighbours in the formation and
functioning of tissues and organs. They do this by interacting with the surface
of other cells or by binding to molecules that other cells are secreting, then
passing on these messages, for example to the cell nucleus where specific genes
are activated or silenced accordingly (see Inside Science No. 122).
Policing the Body
Immunity and Allergy
To take just one example, receptors in the plasma membrane of immune cells
called T lymphocytes or T cells allow them to “police” the body,
recognising and destroying cells that have been invaded by an infectious
organism (see Inside Science No. 7). Their receptors bind to so-called MHC
molecules on the surface of other cells. The MHC molecules present fragments of
proteins or peptides. Healthy, uninfected cells present their own
peptides, but infected cells also present peptides made by the invading
organism. Whereas T cells do not normally respond to MHC molecules associated
with “self” peptides, they trigger a full-scale immune response if their
receptors encounter MHC molecules in association with foreign peptides.
If the T cells mistakenly react to self peptides, this results in an
autoimmune disease such as arthritis or multiple sclerosis. In a similar vein,
if T cells react to peptides that are foreign but otherwise harmless, the result
is an allergic response, such as asthma or hayfever (see Inside Science No.
127). Another, indirect consequence of our immune cell receptors’ ability to
recognise foreign peptides is the body’s rejection of transplanted organs and
tissues. Because MHC molecules vary enormously between individuals, the immune
system recognises those that are not its own as foreign antigens.
Making it possible for immune cells to police our bodies is just one of the
membrane’s key roles. With the publication of the first draft of the human
genome sequence, biologists now have the key that will unlock more and more of
its secrets. The sequence of bases in individual genes indicates the sequence of
amino acids in the proteins they encode, and around a fifth of the genome may
code for transmembrane proteins. Once we know the amino acid sequence of
receptors, ion channels and carrier proteins—and once we have learnt more
about how these proteins fold up to create 3-D shapes—we can begin to
solve the mystery of how they work. Over time we will learn to manipulate cells
and treat disease with ever greater precision, by creating drugs tailor-made to
interact with specific membrane proteins. We and our plasma membranes are truly
living in exciting times.
More is known about the plasma membrane of human red blood cells than any
other membrane. Biologists have been able to use them to discover a huge amount
about the structure of the bilayer, the proteins it contains and its
permeability to various substances. Thanks to red blood cells, the functions of
many proteins that are widespread in the plasma membrane of other cells, such as
channels and proteins that link the membrane to the cytoskeleton, have been
elucidated.
There are several reasons for these cells’ popularity among biologists. They
are available in large numbers (from blood banks) and they are easily separated
from other blood cell types. And because red blood cells have no nucleus or
internal organelles, researchers can be sure that they are only dealing with
plasma membrane—in other cell types, only 5 per cent of the cell’s
membranes are plasma membrane.
Empty red blood cell “ghosts” are prepared by placing cells in a solution
with a lower salt concentration than that of the cytoplasm. Water floods into
the cells through osmosis, making them swell up and burst, releasing their main
non-membrane protein, haemoglobin, and other cell contents that could disrupt
membrane experiments. While it is still broken, both faces of the membrane can
be studied by exposing them to reagents. Such cells are known as “leaky ghosts”.
Alternatively, the cells can be allowed to seal up again, so that reagents can
only reach the outer face of the membrane. A third option is to create
“inside-out ghosts”, in order to study the inner face in isolation.
UP TO 15 per cent of the world’s population suffer from peptic
ulcers—painful lesions in the mucous membrane that lines the stomach and
duodenum. Ulcers are caused when the mucous membrane’s ability to resist the
corrosive effects of stomach acid is compromised, either by the gut bacterium
Helicobacter pylori, by non-steroidal anti-inflammatory drugs taken
to ease the pain of arthritis, or by smoking. Drugs that inhibit acid secretion
in the gut are effective treatments for peptic ulcers
(see Figure 1).
These “acid pump inhibitors” work by blocking hydrogen ion pumps in the
membranes of parietal cells—acid-secreting cells in the glands of
the stomach lining. The pumps actively transport hydrogen ions across the
membrane in exchange for potassium ions, splitting ATP in the process. As a
result, hydrogen ions may reach concentrations a million times higher outside
the cells compared with their cytoplasm. Parietal cells also transport chloride
ions from the blood to the stomach, where they combine with the hydrogen ions to
make hydrochloric acid. Drugs that block the hydrogen pump, such as omeprazole
and lansoprazole, significantly reduce acid production in the stomach and help
to protect its lining.
Antibiotics that eliminate H. pylori are also proving an effective
treatment for peptic ulcers, but other approaches i