2 Americans Share Nobel Prize for Biochemical Discoveries

Chemistry prize rewards research on sensors at the surface of cells.
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2012 nobel winners

Robert J. Lefkowitz (left) and Brian K. Kobilka (right) were awarded the 2012 Nobel Prize in chemistry for their work on gene protein coupled receptors, or GPCRs, shown at center.

Chris J. Nicolini via public domain images

http://bit.ly/QafmwK | Created via public domain and NIH.gov images

Chris Gorski, Editor

(Inside Science) -- The 2012 Nobel Prize in chemistry has been awarded to two physician-chemists "for studies of G-protein-coupled-receptors," proteins that sense compounds outside the cell and activate important signals and cell responses.

The prize goes jointly to Robert J. Lefkowitz of the Howard Hughes Medical Institute and Duke University Medical Center, in Durham, N.C., and Brian K. Kobilka of the Stanford University School of Medicine, in Calif.

The family of receptors the two identified and defined -- also called GPCRs -- include over 1,000 individual receptors responsible for transferring to the cell information about everything from sight, smell, and taste to heart rate regulation, pain tolerance and more. This transfer of information is vital to the cells and the organism they comprise.

The discovery of G-proteins and their workings inside the cell's boundaries was already awarded a Nobel Prize in physiology or medicine in 1994. However, the receptors make it possible to transfer vital information from outside the cell to its interior. The findings have enormous implications for basic body functions.

"A large proportion -- some say 50 percent of all pharmaceuticals used today -- rely on action targeting GPCRs, so knowing what they look like and how they function will provide us with the tools to make better drugs with fewer side effects," chairman of the Nobel Committee for chemistry Sven Lidin said during the announcement ceremony this morning in Stockholm, Sweden.

Many widely used drugs act on GPCRs, including beta blockers, which treat blood pressure and the heart; antihistamines, which primarily treat allergies; and psychiatric medications. But that's just the beginning of what they do. These receptors act as the building blocks of senses; they enable the sensing of adrenalin, dopamine, serotonin, light, flavor, and odor.

"[GPCRs are] a door into the house," said Krishna Rajarathnam, a biochemist at the University of Texas Medical Branch in Galveston. "It's like turning a key."

"I think there are several things that make receptor use so useful in medicine," Lefkowitz said by phone during the announcement ceremony. "[T]hey are crucially positioned to regulate almost every known physiological process in humans. And of course as physicians, what we need to do in cases of disease is to manipulate the activity of these normal substances, like adrenalin, serotonin, dopamine -- the diversity of substances in our body that work through this mechanism that makes them so crucially positioned to be able to respond to drugs of various types."

Lefkowitz began his research in this area in the late 1960s, beginning by attaching radioactive iodine atoms to hormones. This enabled him to begin identifying receptors, beginning with one that processes adrenalin. Brian Kobilka joined his laboratory at Duke in the 1980s. That's when they began finding the genes that code for the receptors. Genes enable a cell to join together amino acids to form a protein. Finding the gene or genes enabled them to better understand how the receptor worked.

What they eventually discovered was that the shape of the adrenalin receptor corkscrewed through the cell wall seven times. This was strikingly similar to the receptor rhodopsin, found in the retina of the eye, which is responsible for sensing light. This led Lefkowitz and Kobilka to conclude that these receptors and many others were part of a large group that functioned in similar ways.

Many other scientists have since worked on GPCRs to illuminate even more of the molecular workings of the cell. Last year, Kobilka managed to create the first image of the receptor, capturing the moment that the receptor transferred the signal from the outside of the cell to a G-protein on the inside.

"They're persistent pursuers, which are hallmarks of really great scientists," said Rajarathnam. "Any discoveries and any treatments can't happen without advances in basic sciences like the ones these two pioneers were able to do."

Of the several hundred GPCRs scientists have identified, they are still trying to identify the purposes of about 100.

 

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Chris Gorski is the Senior Editor of Inside Science. Follow him on twitter at @c_gorski.