MEMBRANE AND SIGNAL TRANSDUCTION

A group seminar presentation

Course code: BCH 625
Course: Membrane Biophysics
Presented by;

OKESINA, Akeem Ayodeji (04/46KA046)

ADENIYI, Philip Adeyemi (05/46KA092)
ADEKOMI Damilare Adedayo (04/48KC194)
POPOOLA Niyi Abdulgafar (02/47KA068)
OYEDEPO Kolade Emmanuel (02/47KA063)

Department of Biochemistry, University of Ilorin,

Ilorin, Nigeria.

Lecturer: Dr. R. Arise

July, 2010
 Table of Content

• Title Page
• Introduction to Membrane
• Structure of Membrane
• Function
• Historical Background of Signal Transduction
• Signal Transduction
• Stages of Cell Signalling
• References
 MEMBRANE

INTRODUCTION
The plasma membrane is composed primarily of two types of molecules—
lipids, which are fatty or oily molecules, and proteins. The basic structural
framework of the plasma membrane is formed by two sheets of lipids, each
sheet a single molecule thick. Within this double layer, or bilayer, of lipids, the
protein molecules are embedded. Proteins are responsible for a host of
functions, including transporting substances across the membrane, aiding
communication between cells, and carrying out chemical reactions. In most
cells, the plasma membrane is about 40 percent lipid and 60 percent protein, but
these proportions vary greatly, from as little as 20 percent to as much as 75
percent protein depending on the type of cell (Farabee 2007)
STRUCTURE

Most of the lipids in the plasma membrane are of a specific type known as
phospholipids. A phospholipid molecule has a head region at one end that is
hydrophilic—it can mix with water. At the other end are two long tails that are
hydrophobic—they do not mix well with water. In the plasma membrane’s
bilayer construction, phospholipid molecules are arranged so that their
hydrophilic heads point outward on either side of the membrane, and their
hydrophobic tails point toward each other in the middle of the membrane. This
orientation keeps the hydrophobic tails away from the watery fluids that both
fill and surround living cells. In fact, the plasma membrane stays intact
precisely because the phospholipid molecules strongly resist any change in
configuration that would expose their hydrophobic tails to the watery
environment. (Farabee 2007)

While the phospholipids are held in a bilayer, scientists believe the plasma
membrane as a whole is a fluid structure because phospholipid molecules and
some proteins can move sideways within the membrane. In one second, a single
phospholipid molecule can travel the length of a large bacterial cell. Proteins
drift more slowly through the membrane. With protein molecules scattered
among the phospholipid molecules, the plasma membrane appears to be a
mosaic of phospholipids and proteins. Some of the proteins are found on the
inner or outer surface of the plasma membrane, while others span the membrane
and protrude on either end. Scientists refer to this concept of the plasma
membrane’s structure as the fluid mosaic model. (Farabee 2007)

The movement of the phospholipid and protein components through the plasma
membrane permits the membrane to change shape. This flexibility is crucial to
many different types of cells. For example, a single-celled organism known as
an amoeba moves by changing shape, stretching out one part of the cell in the
direction of travel and dragging the rest along behind. Human red blood cells
readily change shape as they squeeze through the body’s smallest blood vessels.
(Farabee 2007)

In animal cells, cholesterol also contributes to the fluidity of the plasma

membrane. Cholesterol is a small lipid molecule that nestles among the
hydrophobic tails of the phospholipids in the interior of the membrane. It
prevents phospholipid molecules from packing together too tightly and making
the membrane rigid. It also acts as an “antifreeze” for the plasma membrane,
preventing the membrane from freezing to a jellylike consistency at low
temperatures. Plants and fungi have similar molecules that increase the fluidity
of their plasma membranes. (Farabee 2007)

The lipid and protein molecules that make up the plasma membrane are
manufactured inside the cell and routed to the cell surface. The membrane is a
dynamic structure, with molecules constantly being added to and removed from
the plasma membrane as a cell moves and grows. (Farabee 2007)

(www.lookfordiagnosis.com)
 (www.ucl.ac.uk/sjjgsca/cells.)

FUNCTION

1. ALLOW TRANSPORT OF MATERIALS ACROSS IT:

The plasma membrane forms an extremely effective seal around the cell. Only a
very few molecules can pass directly through the lipid bilayer to get from one
side of the membrane to the other. Many substances that a cell needs in order to
survive cannot cross the lipid bilayer on their own, including glucose (a sugar
that cells burn for energy), amino acids (the building blocks of proteins), and
ions, such as sodium and potassium. A cell uses two methods to move such
substances from one side of the plasma membrane to another, known as passive
transport and active transport. Both of these processes involve proteins in the
plasma membrane. (Farabee 2007)

Passive transport is accomplished by diffusion, the spontaneous movement of a

substance from a region of greater concentration to a region of lesser
concentration. The difference between the concentration of a substance in two
different areas is known as a concentration gradient. Diffusion moves
molecules down a concentration gradient in a manner that does not require the
cell to expend energy. Water, oxygen, carbon dioxide, and a few other small
molecules diffuse directly across the plasma membrane by passing
between(Farabee 2007)

phospholipid molecules. Substances that cannot pass directly through the

plasma membrane diffuse into or out of cells with the aid of hollow, channel-
like proteins in a process known as facilitated diffusion. These channel proteins
are shaped so that only one substance, or a small group of closely related
substances, can pass through each type of protein. This specificity enables a cell
to control precisely the molecules that travel in and out of the cell. (Farabee
2007)

In order to move substances against a concentration gradient—that is, from the

side of the plasma membrane where the concentration of a substance is lower to
the side where it is already higher—a cell must expend energy in a process
known as active transport. Active transport is achieved by membrane proteins
called pumps, which have a docking site that is shaped to fit a specific
substance. These pumps are open on either the inside or the outside of the cell.
When the proper molecule or ion attaches to the docking site, the pump changes
shape so that the docking site moves its opening to the other side of the plasma
membrane, releasing the molecular cargo. Many pumps obtain the energy
necessary to perform this work from adenosine triphosphate (ATP), a molecule
that serves as the main energy currency of living cells. (Farabee 2007)

Two additional transport mechanisms provide pathways for large molecules to

pass in and out of cells. In endocytosis, the plasma membrane folds inward,
forming a pouch that traps molecules. The pouch continues to press inward until
it forms a closed sac that breaks loose from the plasma membrane and sinks into
the cell. The second mechanism, exocytosis, is a reversal of endocytosis. A sac
inside the cell containing proteins and other molecules moves toward the outer
edge of the cell until it touches the plasma membrane. The membrane of the sac
then joins with the plasma membrane, and the contents of the sac are released
from the cell. Most of the proteins released by animal cells, such as hormones
and antibodies, exit the cells where they are made through exocytosis. (Farabee
2007)

2. COMMUNICATION BETWEEN CELLS:

In multicellular organisms, the plasma membrane also plays a critical role in

communication between cells. Proteins embedded in the plasma membrane act
as receptors, binding to hormones and other molecules sent as signals from
other cells. In animal cells, certain membrane proteins also act as markers that
help the immune system distinguish the body’s own cells from foreign cells.
These marker proteins help trigger the immune reaction that protects humans
and other animals from disease-causing organisms such as bacteria, viruses, and
fungi. These markers also play a role in the rejection of transplanted tissues and
organs. (Farabee 2007)

3.IT ALSO HELP IN HOLDING THE CELLS TOGETHER:

In certain types of cells, the plasma membrane has a wide variety of additional
functions. Some membrane proteins are involved in holding neighbouring cells
together. (Farabee 2007)

HISTORICAL BACKGROUND OF SIGNAL TRANSDUCTION

Cells from nerves, glands, and other tissues communicate with each other by
releasing hormones or other substances that act as chemical signals. In research
conducted in the 1960s and 1970s, Rodbell of the National Institute of
Environmental Health Sciences had demonstrated that cells bind the cellular
molecule guanosine triphosphate (GTP) to their surfaces. This binding activates
the transduction, or conversion, of the exterior message to an internal message
that then triggers a chemical activity inside the cell. (

"signal transduction." A
Dictionary of Biology. 2004. Retrieved July 09, 2010 from Encyclopedia.com: http://www.en
cyclopedia.com/doc/1O6-signaltransduction.html).

Gilman built on Rodbell's work by identifying the protein to which GTP can
bind. Experimenting with mutated leukemia cells, Gilman showed that even
though the cells had all the necessary receptors for transmitting a message from
outside to inside the cell, they were unable to do so. After many years of work,
he and his colleagues isolated a protein that, when added to the cell's membrane,
bound GTP and restored the message-transducing function in the mutated cell.
Because GTP was bound by this protein, Gilman named it the G-protein. Since
Gilman's original discovery, many different types of G-proteins have been
found. The senses of smell, taste, and sight rely on G-proteins to transmit
information along nerve cells. Other G-proteins regulate cell metabolism and
control cell division. (
"signal transduction." A Dictionary of Biology. 2004. Retrieved July 09, 2010 from
Encyclopedia.com: http://www.encyclopedia.com/doc/1O6-signaltransduction.html).

Some diseases can alter the functioning of G-proteins. Cholera, for instance,
produces a toxic enzyme that affects the G-proteins present in the cells of the
intestine, interfering with the ability of the cells to absorb water and salt that the
body needs. Left unchecked, this condition leads to rapid dehydration and death.
G-proteins may also play a part in some symptoms associated with diabetes and
alcoholism. Certain genetic disorders can cause cells to have too many or too
few G-proteins, thereby altering cell function in an adverse way. (

"signal
transduction." A Dictionary of Biology. 2004. Retrieved July 09, 2010 from Encyclopedia.co
m: http://www.encyclopedia.com/doc/1O6-signaltransduction.html).

As well as other honours, Gilman has also received the Albert Lasker Basic
Medical Research Award (1989). Gilman currently chairs the Department of
Pharmacology at the University of Texas Southwest Medical Center in Dallas. (

"signal transduction." A Dictionary of Biology. 2004. Retrieved July 09, 2010 from
Encyclopedia.com: http://www.encyclopedia.com/doc/1O6-signaltransduction.html).

In the 1940s and 1950s Sutherland studied the hormones epinephrine and
glucagon. Both were known to play a role in releasing glucose (sugar) in the
liver, which the body uses as a source of energy. The exact mechanism of their
action, however, was not understood. In a series of experiments in the 1950s,
Sutherland discovered the molecule cyclic AMP and its role in this process. He
uncovered a chain of chemical reactions that began outside the cell and
continued within it to convert glycogen (stored sugar) to glucose. These
reactions begin when hormones attach, or bind to specific sites on the outside of
a cell membrane. This activates the enzyme (proteins that cause or accelerate
chemical reactions) adenylate cyclase within the cell membrane, which in turn
triggers the release of cyclic AMP within the cell. Cyclic AMP then changes an
inactive enzyme phosphorylase to its active form, which causes glycogen to be
converted to glucose. Sutherland described the hormones in this process as a
first messenger, and cyclic AMP and other intermediates as second messengers.
When he and others found this same reaction in both simple bacteria and
humans, it became clear that this mechanism had been conserved through
evolution over millions of years. Sutherland studied cyclic AMP thoroughly, as
well as another second-messenger molecule known as guanosine
monophosphate (cyclic GMP). Sutherland's discoveries laid the foundation for
the work of today's biochemists and molecular biologists studying signal
transduction (information relayed to the nucleus of the cell via chemical signals,
such as hormones), which has relevance to medical diagnosis, drug
development, and gene therapy. (

"signal transduction." A Dictionary of Biology. 2004. Retrieved July 09, 2010 from
Encyclopedia.com: http://www.encyclopedia.com/doc/1O6-signaltransduction.html).

Sutherland received many honours for his discoveries. He was elected to the
U.S. National Academy of Sciences in 1966. He won both the Gairdner
International Foundation Award and the Albert Lasker Basic Medical Research
Award in 1970. (

"signal transduction." A Dictionary of Biology. 2004. Retrieved July 09,

2010 from Encyclopedia.com: http://www.encyclopedia.com/doc/1O6-
signaltransduction.html).

SIGNAL TRANSDUCTION

Signal transduction originates at the membrane, where the clustering of

signalling proteins is a key step in transmitting a message. Membranes are
difficult to study, and their influence on signalling is still only understood at the
most rudimentary level. Recent advances in the biophysics of membranes,
surveyed in this review, have highlighted a variety of phenomena that are likely
to influence signalling activity, such as local composition heterogeneities and
long-range mechanical effects.Signal transduction‘Any
mechanism by which binding of an extracellular signal
molecule to a cell-surface receptor triggers a response
inside the cell.’

The mechanism depends on the type of signal molecule (e.g. hormone,

paracrine, or autocrine signals), but it often involves changes in concentration of
a second messenger (e.g. cyclic AMP, calcium ions) within the cell, which in
turn can affect numerous cell activities. Many receptors are associated with G
proteins, which act to turn signal transduction pathways on and off. Other
important components of signal transduction include protein kinases, which
activate enzymes by transferring a phosphate group from ATP (
"signal
transduction." A Dictionary of Biology. 2004. Retrieved July 09, 2010 from Encyclopedia.co
m: http://www.encyclopedia.com/doc/1O6-signaltransduction.html).

Cells usually communicate by releasing chemical messengers targeted for cells

that may not be immediately adjacent. Some messengers travel only short
distances. Such molecules are called local regulators: a substances that
influences cells in vicinity. E.g. animal growth factors, which are compounds
that stimulate nearby target cells to grow and multiply. Numerous cells can
simultaneously receive and respond to the molecules of growth factors produced
by a single cell in their vicinity. This type of local signalling in animals is called
paracrine signalling.(" A Dictionary of Biology. 2004. Retrieved July 09, 2010 from Enc
yclopedia.com: http://www.encyclopedia.com/doc/1O6-signaltransduction.html).

Another specialized type of local signalling occurs between nerve cells. One
nerve cell produces a neurotransmitter, that diffuses (across a synapse) to a
single target cell that is touching the first cell. " (A Dictionary of Biology. 2004. Retri
eved July 09, 2010 from Encyclopedia.com: http://www.encyclopedia.com/doc/1O6-
signaltransduction.html).

Both animals and plants use chemicals called hormones for signalling at greater
distances. Cells may also communicate by direct contact. Both animals and
plants have cell junctions that provide cytoplamic continuity between adjacent
cells. Also, animal cells may communicate via direct contact between molecules
on their surfaces. This sort of signalling is important in embryonic development
and in the operation of the immune system. (" A Dictionary of Biology. 2004. Retriev
ed July 09, 2010 from Encyclopedia.com: http://www.encyclopedia.com/doc/1O6-
signaltransduction.html).
(" A Dictionary of Biology. 2004. Retrieved July 09, 2010 from Encyclopedia.com: http://ww
w.encyclopedia.com/doc/1O6-signaltransduction.html).

STAGES OF CELL SIGNALLING.

From the perspective of the cell receiving the message, cell signalling can be
divided into three stages: Signal reception, Signal transduction, and Cellular
response. When reception occurs at the plasma membrane, the transduction
stage is usually a pathway of several steps, with each molecule in the pathway
bringing about a change in the next. The last molecule in the pathway triggers
the cell's response.( A Dictionary of Biology. 2004. Retrieved July 09, 2010 from Encyclo
pedia.com: http://www.encyclopedia.com/doc/1O6-signaltransduction.html).
" A Dictionary of Biology. 2004. Retrieved July 09, 2010 from Encyclopedia.com:
http://www.encyclopedia.com/doc/1O6-signaltransduction.html).

SIGNAL RECEPTION AND THE INITIATION OF TRANSDUCTION

A signal molecule binds to a receptor protein, causing the protein to change

shape. A cell targeted by a particular chemical signal has molecules of a
receptor protein that recognizes the signal molecule. The signal molecule is
complementary in shape to a specific site on the receptor and attaches there, like
a key in a lock. The signal molecule behaves as a ligand, the term for a small
molecule that specifically binds to a larger one. Ligand binding causes a
receptor protein to undergo a change in conformation, that is a change in shape.
For many receptors, this shape change directly activates the receptor so that it
can interact with another cellular molecule. For other receptors the immediate
effect of the ligand binding causes the aggregation of two or more receptor
molecules. (Gilman, 1987).

MOST SIGNAL RECEPTORS ARE PLASMA-MEMBRANE PROTEINS.

G-Protein-Linked Receptors. This is a plasma-membrane receptor that works

with the help of a protein called a G protein and another protein, usually an
enzyme. In the absence of the extracellular signal molecule specific for the
receptor, all three proteins are in inactive form. The inactive G protein has a
GDP molecule bound to it. When the signal molecule binds to the receptor
protein, the receptor changes shape in such a way that it binds and activates the
G protein. A molecule of GTP replaces the GDP on the G protein. The active G
protein (moving freely along the membrane) binds to and activates the enzyme,
which triggers the next step in the pathway leading to the cell's response. The G
protein then catalyzes the hydrolysis of its GTP and dissociates from the
enzyme, becoming available for reuse. All three proteins remain attached to the
plasma membrane. (Gilman, 1987).
 (Gilman, 1987).
Tyrosine-Kinase Receptors. In the absence of specific signal molecules,
tyrosine-kinase receptors exist as single polypeptides in the plasma membrane.
The extracellular portion of the protein, with the signal-molecule binding site, is
connected by a single transmembrane helix to the protein's cytoplasmic portion.
This part of the protein is responsible for the receptor's tyrosine-kinase activity
and also has a series of tyrosine amino acids. When signals molecules (such as a
growth factor) attach to their binding sites, two polypeptides aggregate, forming
a dimer. Using phosphate groups from ATP, the tyrosin-kinase region of each
polypeptide phosphorylates the tyrosines on the other polypeptide. In other
words, the dimer is both an enzyme and its own substrate. Now fully activated,
the receptor protein can bind specific intracellular proteins, which attach to
particular phosphorylated tyrosines and are themselves activated. Each can then
initiate a signal-transduction pathway leading to a specific cellular response.
Tyrsine-kinase receptors often activate several different signal-tranduction
pathways at once, helping regulate such complicated functions as cell
reproduction (cell divisions). Inappropriate activation of these receptors can
lead to uncontrolled cell growth - cancer. (Li and Hristova 2006)

(Li and Hristova 2006)

Ion-Channel Receptors. Some membrane receptors of chemical signals are
Ligand-gated ion channels. These channels are protein pores in the plasma
membrane that open or close in response to the binding of a chemical signal,
allowing or blocking the flow of specific ions, such as Na+ or Ca2+ into the cell.
Often the change in the concentration of a particular ion inside the cell directly
affects cell function. (Hille, 2001).

(Hille, 2001).

Intracellular Receptors. Not all signal receptors are membrane proteins. Some
are proteins located in the cytoplasm or nucleus of target sells. To reach such a
receptor, a chemical messenger must be able to pass through the target cell's
plasma membrane. A number of important signaling molecules can do just that,
either because they are small enough to pass between the membrane
phospholipids or because they are themselves lipids and therefore soluble in the
membrane. (Albert et al 2002)

Signal-Transduction Pathways

The transduction stage of cell signalling is usually a multistep pathway. One

benefit of such a pathway is signal amplification. If some of the molecules in a
pathway transmit the signal to multiple molecules of the next component in the
series, the result can be a large number of activated molecules at the end of the
pathway. That is a very small number of extracellular signal molecules can
produce a major cellular response. (Schlessinger, 1988)

Pathways relay signals from receptors to cellular responses. Like falling

dominoes, the signal-activated receptor activates another protein, which
activates another molecule, and so on, until the protein that produces the final
cellular response is activated. The molecules that relay a signal from the
receptor to response, sometimes called relay molecules, are mostly proteins.
(Schlessinger, 1988)

Protein phosphorylation, a common mode of regulation in cells, is a major

mechanism of signal transduction. A signalling pathway begins when a signal
molecule binds to a membrane receptor. The receptor then activates a relay
molecule, which activates a protein kinase (1). Active protein kinase 1 transfers
a phosphate from ATP to an inactive molecule of another protein kinase
molecule (2), thus activating this second kinase. In turn, active protein kinase 2
catalyzes the phosphoralation (and activation) of protein kinase 3. Finally,
active protein kinase 3 phosphorylates a protein that brings about the cell's final
response to the signal. Each activated protein kinase molecule is inactivated by
the removal of tha phosphate group by enzymes called phosphatases. This make
the protein kinases available for reuse. (Schlessinger, 1988)
 (Schlessinger, 1988)

Second Messengers

Certain small molecules and ions are key components of signaling pathways
(second messengers). The extra cellular signal molecule that binds to the
membrane receptor is a pathway's "first messenger". Because second
messengers are both small and water-soluble, they can readily spread
throughout the cell by diffusion. Second messangers participate in pathways
initiated by both G-protein-linked receptors and tyrosine-kinase receptors. The
two most widely used second messengers are cyclic AMP and calcium ions,
Ca2+. A large variety of relay proteins are sensitive to the cytosolic
concentration of one or the other of these second messengers. (Hanna et al
1984)

Cyclic AMP (cAMP) Cyclic AMP is a component of many G-protein-signaling

pathways. The signal molecule - the "first messanger" - activates a G-protein-
linked receptor, which activates a specific G protein. In turn, the G protein
activates adenylyl cyclase, which catalyzes the conversion of ATP to cAMP.
(Hanna et al 1984).

(Hanna et al 1984)

Calcium Ions and Indositol Triphosphate Calcium ions (Ca2+) are actively
transported out of the cytosol by a variety of protein pumps. Pumps in the
plasma membrane move Ca2+ into the extracellular fluid, and ones in the ER
membrane Ca2+ into the lumen of the ER. Consequently, the Ca2+ consentration
in the cytosol is usually muth lower than in the extracellular fluid and ER.
Additional Ca2+ pumps in the mitochondrial inner membrane operate when the
calcium level in the cytosol rises significantly. These pumps are driven by the
proton-motive force generated across the membrane by mitochondrial electron
transport chains. Calcium ions (Ca2+) and indositol trisphosphate (IP3) functions
as second messengers in many signal-transduction pathways. The process is
initiated by thebinding of a signal molecule to either a G-linjed receptor or a
Tyrosine-kinase receptor. In The following figure the circled numbers trace the
former pathway. 1- Asignal molecule binds to a receptor, leading to 2-
activation of an enzyme celled phospholipase C. 3- This enzyme cleaves a
plasma-membrane phospholipid called PIP2 into DAG and IP3. Both can
function as second messangers. 4- IP#, a small molecule, quickly diffuses
through the cytosol and binds to a ligand-gated calcium channel in the ER
membrane, causing it to open. 5- Calcium ions flow out of the ER (down their
gradient), raising the Ca2+ level in the cytosol. 6- The calcium ions activate the
next protein in one or more signaling pathways, often acting via calmodulin,
aubiquitous Ca2+-binding protein. DAG functions as a second mesanger in still
other pathways. (Hanna et al 1984)

(Hanna et al 1984)

Cellular Response to Signals

Ultimateley, a signal-transduction pathway leads to the regulation of one or

more cellular activities. The regulated activities may occur in the cytoplasm,
such as a rearrangment of the cytoskeleton, the opening or closing of an ion
channel in the plasma membrane, or some aspect of cell metabolism. Many
other signaling pathways ultimately regulate not the activity of an enzyme but
the synthesis of enzymes or other proteins, usually by turing specific genes on
or off. (King et al 2003)
(King et al 2003)
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