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Press Release: The 1994 Nobel Prize in Physiology or
Medicine
NOBELFÖRSAMLINGEN KAROLINSKA INSTITUTET
THE NOBEL ASSEMBLY AT
THE KAROLINSKA INSTITUTE
10 October 1994
The Nobel Assembly at the
Karolinska Institute has today decided to award the Nobel Prize
in Physiology or Medicine for 1994 jointly to
Alfred G.
Gilman and Martin Rodbell
for their discovery of
"G-proteins and the role of these proteins in signal transduction in
cells".
Summary
It has been known for
some time that cells communicate with each other by means of
hormones and other signal substances, which are released from
glands, nerves and other tissues. It is only recently that we have
begun to understand how the cell handles this information from the
outside and converts it into relevant action - i.e. how signals are
transduced in cells.
The discoveries of the G-proteins by
the Americans Alfred G. Gilman and Martin Rodbell have
been of paramount importance in this context, and have opened up a
new and rapidly expanding area of knowledge.
G-proteins have
been so named because they bind guanosine triphosphate (GTP). Gilman
and Rodbell found that G-proteins act as signal transducers, which
transmit and modulate signals in cells. G-proteins have the ability
to activate different cellular amplifier systems. They receive
multiple signals from the exterior, integrate them and thus control
fundamental life processes in the cells.
Disturbances in the
function of G-proteins - too much or too little of them, or
genetically determined alterations in their composition - can lead
to disease. The dramatic loss of salt and water in cholera is a
direct consequence of the action of cholera toxin on G-proteins.
Some hereditary endocrine disorders and tumours are other examples.
Furthermore, some of the symptoms of common diseases such as
diabetes or alcoholism may depend on altered transduction of signals
through G-proteins.
Signal transduction in
cells
We are made up of thousands of billions of cells
that must act in concert to allow us to perform our daily activities
and to meet challenges. This cooperation is achieved partly by cells
communicating with each other through chemical signals. Hormones and
other signal molecules are released from glands, nerves and other
tissues. The chemical signals attach to specific recognition
molecules, receptors, on the cell surface. These receptors
transmit the signals to the interior of the cell. The important
features of the communication between cells have been known
for some time. On the other hand, the transduction of signals in
cells was unclear until Alfred G. Gilman and
Martin Rodbell made their discoveries.
The cell
is surrounded by a membrane, largely composed of lipids, that
effectively separates the outside of the cell from its inside. Earl
Sutherland, USA, received the Nobel Prize in 1971 for his
discoveries concerning the mechanism of action of hormones. He
showed that the signal that is used to communicate between cells
("the first messenger") is converted to a signal that acts inside
the cell ("the second messenger"). It was known that this signal
conversion occurred in the cell membrane, but not much more was
understood about the processes involved.
Martin
Rodbell and his coworkers at the National Institutes of Health in
Bethesda, USA, demonstrated, in a set of pioneering experiments
conducted in the late 1960's and early 1970's, that the signal
transduction through the cell membrane involves a cooperative action
of three different functional entities (Fig. 1).
It all
starts with the chemical signal binding specifically to its receptor
in the cell membrane. Since the receptor determines which signal
molecules it will bind it functions, to use Rodbell's nomenclature,
as a discriminator.
The amplifier generates
large amounts of the intracellular "second messenger", for example
cyclic AMP. Rodbell was one of the first to realize that the
discriminator/receptor was distinct from the amplifier. However, his
major discovery was the demonstration of a separate
transducer function. It provides a link between the
discriminator and the amplifier and thus plays a key role in signal
transduction. Rodbell found that the transducer was driven by
guanosine 5'-triphosphate, GTP, an energy rich compound. He also
found that there may be several
transducers.
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Figure 1. Martin Rodbell showed in 1971
that the transduction of a message from the exterior of the cell to
its interior requires the cooperation of three functional units: 1)
a discriminator (receptor) that recognizes different extracellular
signals (first messengers), 2) a transducer that requires GTP, and
3) an amplifier that generates large quantities of a second
messenger.
Alfred G. Gilman, working at the University of Virginia in
Charlottesville, USA, decided to determine the chemical nature of
Rodbell's transducer. He used several kinds of leukemia cells with
altered genetic setup. Gilman found that one mutated leukemia cell
possessed a normal receptor and a normal amplifier protein that
generated cyclic AMP as a second messenger. Despite this, the cell
failed to respond normally when challenged with signals from outside
- nothing happened.
Gilman showed that these mutated cells
lacked the transducer function. After many years of work, he and his
collaborators during the latter years of the 1970's found - and in
1980 eventually purified - a protein in normal cells that when
transferred into the membrane of the cell defective cell restored
its function (Fig 2).
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Figure 2. Alfred Gilman and his coworkers
used leukemia cells to identify and demonstrate G-proteins. Normal
leukemia cells respond with a normal biological response to the
appropriate first messenger. In mutated cells, however, no response
was evoked, because the cells lacked the G-protein. The function
could be restored by G-protein derived from another tissue such as
brain.
Thus, the first G-protein was discovered. It was
given the name now commonly used, G-protein, because it reacts with
GTP. Due to the discoveries of Gilman and Rodbell and their work,
several laboratories turned to the area. Therefore we now know a
great deal about the functions of G-proteins and how they control
the activities of the cell.
A protein in shuttle
service
G-proteins are composed of three separate peptide
chains of different length, each existing in multiple forms. They
are denoted alpha, beta and gamma, the first three letters of the
Greek alphabet. All three are encoded by specific genes in the cell
nucleus. Combinations of the different peptide chains allow the
generation of some hundred different G-proteins. The alpha subunit,
which is the largest, can bind GTP. When that happens, in a process
stimulated by the receptor, the G-protein is converted to its active
form. In this form it can turn on the formation of the second
messenger, for example cyclic AMP. The G-protein converts GTP to GDP
and reverts to an inactive form (Fig 3). The G-protein thus shuttles
between the hormone receptor and the amplifier system in the cell
membrane, being alternatively switched on or off.
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Figure 3. G-proteins act as molecular
switches. The hormonal signal allows the G-protein to exchange GDP
for GTP. The G-protein is thereby activated and several different
amplifier systems can be activated. This leads to different changes
in the cell. The signal is switched off again as GTP is converted to
GDP.
There are thus several types of G-proteins. Each is
activated by only some receptors and can in turn stimulate some
specific amplifier systems. In this way characteristic responses in
the cells are generated. In the retina of the eye there are specific
G-proteins that convert the light signal to activation of those
nerve fibers that convey visual stimuli to the brain. Our sense of
smell depends on specific G-proteins in the olfactory cells, and the
sensation of taste is related to yet other types of G-proteins.
Some G-proteins stimulate - other inhibit - the formation of
cyclic AMP and hence the cellular metabolism. Some G-proteins alter
the flux of ions over the cell membranes and thus the activity of
the cell. G-proteins affect protein phosphorylation, and exert
control over cell division and differentiation.
G-proteins and disease
Many symptoms
of disease are explained by an altered function of G-proteins. A
prime example is given by cholera, one of the most feared
gastrointestinal infectious diseases. The disease is caused by
cholera bacteria that produce a very poisonous cholera toxin. The
toxin acts as an enzyme that alters one of the G-proteins in such a
manner that it is locked in the active form. The traffic light is
stuck on green. This prevents salt and water to be normally absorbed
from the intestines. The resulting loss of water and salt can lead
to dehydration and death. Symptoms after infection with some coli
bacteria appear to have a similar background. A toxin produced by
pertussis bacteria instead prevents the activation of some
G-proteins. This can lead to a compromised immune defence.
In some common disease states the amounts of G-proteins in
cells are altered. There can be too much or too little of them. In
for example diabetes and in alcoholism there may be some symptoms
that are due to altered signalling via G-proteins.
In
animals it has been shown that a reduced expression of G-proteins
can lead to altered development and to metabolic disturbances. In
man it has been shown that mutated and overactive G-proteins are a
characteristic of some tumors. An overactive G-protein is also found
in a rare genetic endocrine disorder - McCune-Albrights
syndrome- that is also characterized by so called cafe au lait
spots on the skin. Yet another mutation of a G-protein, in this case
causing a reduced activity, leads to disrupted calcium metabolism
and skeletal deformations. |
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