G proteins explained - 1994 News Article

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G proteins explained - 1994 News Article

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It's now been over 25 years since the Nobel Prize for Medicine was given to Martin Rodbell and Alfred G. Gilman for the discovery of G proteins.

Since then, hundreds of drugs have been developed, aimed specifically at G-protein-coupled receptors.

In 2012, another Nobel Prize involving G proteins was given, this time in Chemistry. It was awarded to Robert Lefkowitz and Brian Kobilka for studies of G-protein–coupled receptors.

Half of all current medications achieve their effect by targetting G-protein-coupled receptors. Common examples are beta-blockers or antihistamines.

Yet G proteins remain mysterious and are misunderstood by many.

What are G Proteins?

Below we repost two news items to help answer that question.

The first one is an article from 1994 Boston Globe, the second a press release from 2012, released by the Royal Swedish Academy of Sciences.

Two from US share Nobel Prize in Medicine
'G Proteins' seen key to cell links

By Usha Lee McFarling, Boston Globe Staff
October 11, 1994, Page: 5

Two US scientists won the Nobel Prize in medicine yesterday for their discovery of an intricate internal "switchboard" that allows the body's billions of cells to communicate with one another -- and that unleashes cancer and cholera's devastating effects when it goes awry.

Alfred G. Gilman, of the University of Texas Southwestern Medical Center in Dallas, and Martin Rodbell, of the National Institute of Environmental Health Sciences in North Carolina, won the prize for work they conducted independently in the past three decades to discover the "G proteins" that act as the switchboard of the body's communication pathway... Gilman and Rodbell, 68, will share the prize's $930,000 award...

The realm the Nobel winners studied is the complex relay of cell communication, by which information from the outsides of cells is conveyed to the cells' interior machinery by a series of agents.

G proteins, the most crucial of those agents, have been described as ''biological traffic lights." Lying inside the cell, they can respond to signals from outside the cell -- light, smell, neurotransmitters and hormones -- and translate them into a frenzy of cellular action inside.

While G proteins are little known to the general public, research on them has been one of the hottest biological pursuits of the past decade.

"G proteins are one of the keys to all functions in every cell of the body," Reuters quoted Gosta Gahrton, a professor of medicine at the Karolinska Institute in Stockholm and a member of the prize panel that awarded the prize, as saying.

The proteins are implicated in a growing list of cellular activities -- from mating in yeast to thinking in humans. They permit sight and smell by converting light and scent into messages that can be taken to the brain.

When G proteins do not work, they can lead to symptoms of such diseases as diabetes, alcoholism, cholera and whooping cough. The proteins, which have been called "ubiquitous, influential, and enigmatic," will be the target of medical treatments, the Nobel institute predicted.

At least 17 of the proteins have been discovered. They are called G proteins because they bind to guanine nucleotides, a major component of the genetic molecules DNA and RNA.

Rodbell and his co-workers at the National Institutes of Health determined that guanine nucleotides were involved in cell communication -- a finding that led to the discovery of G proteins. His work in the 1960s and '70s also described how messages like light are converted inside cells, and showed that cells have different components that receive, transport and amplify outside messages.

Rodbell retired in May. He holds the title of scientist emeritus at the National Institutes of Health. Gilman chairs the pharmacology department at the University of Texas Southwestern Medical Center in Dallas and won biology's coveted Lasker award in 1989. Gilman is the fourth UT Southwestern faculty member to win the Nobel Prize.

Gilman and colleages, while working at the University of Virginia in Charlottesville in the 1970s, looked for the chemicals that made up the substances Rodbell described. In 1980, they discovered G proteins.

The field did not blossom until 1984, when the first genes for G proteins were cloned. Since then, more scientists began working with the proteins, and some pharmaceutical companies are now trying to develop drugs targeting G proteins.

In a 1992 Scientific American article on G proteins that Gilman co-wrote with Maurine E. Linder, he predicted that scientists would evenutally diagram the cellular players involved in communication and be able to predict how those cells will operate in response to different combinations of signals.

"For those who would hope to develop drug therapies," the authors said, ''such discoveries would be like giving a thief a wiring diagram to the alarm system at a bank."

============================================================================================================
10 October 2012

The Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Chemistry for 2012 to

Robert J. Lefkowitz
Howard Hughes Medical Institute and Duke University Medical Center, Durham, NC, USA

and

Brian K. Kobilka
Stanford University School of Medicine, Stanford, CA, USA

“for studies of G-protein–coupled receptors”

Smart receptors on cell surfaces

Your body is a fine-tuned system of interactions between billions of cells. Each cell has tiny receptors that enable it to sense its environment, so it can adapt to new situations. Robert Lefkowitz and Brian Kobilka are awarded the 2012 Nobel Prize in Chemistry for groundbreaking discoveries that reveal the inner workings of an important family of such receptors: G-protein–coupled receptors.

For a long time, it remained a mystery how cells could sense their environment. Scientists knew that hormones such as adrenalin had powerful effects: increasing blood pressure and making the heart beat faster. They suspected that cell surfaces contained some kind of recipient for hormones. But what these receptors actually consisted of and how they worked remained obscured for most of the 20th Century.

Lefkowitz started to use radioactivity in 1968 in order to trace cells’ receptors. He attached an iodine isotope to various hormones, and thanks to the radiation, he managed to unveil several receptors, among those a receptor for adrenalin: β-adrenergic receptor. His team of researchers extracted the receptor from its hiding place in the cell wall and gained an initial understanding of how it works.

The team achieved its next big step during the 1980s. The newly recruited Kobilka accepted the challenge to isolate the gene that codes for the β-adrenergic receptor from the gigantic human genome. His creative approach allowed him to attain his goal. When the researchers analyzed the gene, they discovered that the receptor was similar to one in the eye that captures light. They realized that there is a whole family of receptors that look alike and function in the same manner.

Today this family is referred to as G-protein–coupled receptors. About a thousand genes code for such receptors, for example, for light, flavour, odour, adrenalin, histamine, dopamine and serotonin. About half of all medications achieve their effect through G-protein–coupled receptors.

The studies by Lefkowitz and Kobilka are crucial for understanding how G-protein–coupled receptors function. Furthermore, in 2011, Kobilka achieved another break-through; he and his research team captured an image of the β-adrenergic receptor at the exact moment that it is activated by a hormone and sends a signal into the cell. This image is a molecular masterpiece – the result of decades of research.

The Prize amount: SEK 8 million, to be shared equally between the Laureates.

SOURCE:
https://www.nobelprize.org/prizes/chemi ... s-release/

Further Reading:
Wang J, Gareri C, Rockman HA - "G-Protein-Coupled Receptors in Heart Disease" Circ Res 123(6):716-735 (2018)
https://www.ahajournals.org/doi/10.1161 ... 118.311403
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