Announcement: MEDICAL NOBEL PRIZE LAUREATES 1994

[bjorn.vennstrom at POSTMAC.CMB.KI.SE]

MEDICAL NOBEL PRIZE LAUREATES 1994: Announcement


                    PRESS RELEASE, OCTOBER 10, 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 the 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 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.

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.

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. 

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. The 
G-protein thus shuttles between the hormone receptor and the amplifier 
system in the cell membrane, being alternatively switched on or off.

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.



Nils Ringertz
Professor, Secretary of the Nobel Assembly
nils.ringertz at cmb.ki.se
phone +46 8 728 7800

______________________________________________________________________

           NOBEL LAUREATES IN PHYSIOLOGY OR MEDICINE 1994

                         CURRICULA VITAE



ALFRED G. GILMAN, born July 1, 1941, New Haven, Connecticut, USA

      Address: Department of Pharmacology, University of Texas,
      Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 
      Texas 75235, USA

      Academic Education:
      
      1962       B.S. Yale University, New Haven, Connecticut
      1969       M.D. Case Western Reserve Univ School of Med, 
                 Cleveland, 
                 Ohio
      1969       Ph.D. Dept of Pharmacology, Case Western Reserve 
                 University
      1971       Postdoc. Nat'l Heart & Lung Inst., Bethesda, MD

      Appointments and Professional Activities:

      1977-81    Professor of Pharmacology, University of Virginia, 
                 School of Medicine
      1981-      Professor and Chairman, Department of Pharmacology,
                 University of Texas Southwestern Medical Center at 
                 Dallas, Dallas, Texas
      1987-      Raymond and Ellen Willie Professor of Molecular 
                 Neuropharmacology, University of Texas, Southwestern 
                 Medical Center at Dallas
      1992-      Member, National Advisory General Medical Sciences 
                 Council

      Fellowships and Awards:
          
      Gairdner Foundation Award, 1984
      Member, National Academy of Sciences, 1985
      Member, American Academy of Arts and Sciences, 1988
      Albert Lasker Basic Medical Research Award, 1989
      Doctor of Science (Hon.) Univ. of Chicago, 1991


                          *  *  *


MARTIN RODBELL, born December 1, 1925, Baltimore, Maryland

Address:  National Institute of Environmental Health Sciences, 
Building 18-01, P.O. Box 12233, Research Triangle Park, North 
Carolina, 27709, USA

Academic Education: 

1949        BA in Biology, Johns Hopkins University
1949-1950   Post-graduate study in Chemistry, Johns Hopkins
1954        PhD (Biochemistry), University of Washington

Appointments and Professional Activities:

1967-1968   Professor & Director of Institut de Biochemie Clinique, 
            University of Geneva, Switzerland
1981-1983   Visiting Professor, Dept of Clinical Biochemsitry, 
            University of Geneva 
1970-1985   Chief, Section on Membrane Regulation, NIAMDD, NIH, 
            Bethesda, MD
1973-1985   Chief (Senior Executive Service), Laboratory of Nutrition 
            and Endocrinology, NIAMDD, Bethesda, MD
1985-1989   Scientific Director (Senior Executive Service), National
            Institute of Environmental Health Sciences, Research 
            Triangle Park, NC
1989 -      Chief, Section on Signal Transduction: National Institute, 
            Environmental Health Sciences

Fellowships and Awards:

1973        Jacobeaus Award, Acta Scandinavia Society, Oslo, Norway
1984        Gairdner International Award, Toronto, Canada
1984        Award of Scientific Merit, National Institutes of Health
1992        Honoris Doctoris, Montpellier University, France
1993        Luis Harris Distinguished Lecturer, Virgina Medical 
            College

Member, National Academy of Sciences (USA)
Member, European Association for the Study of Diabetes
Member, American Society of Biological Chemists
Member, American Association for the Advancement of Sciences
Member, American Academy of Arts and Sciences


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This posting was done by Bjorn Vennstrom at the request of Prof. 
Ringertz
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