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Chemistry Nobel Awarded for Work on G-Protein-Coupled Receptors (GPCRs)

Robert J. Lefkowitz M.D., a Howard Hughes Medical Institute investigator who has spent his entire 39-year research career at the Duke University Medical Center, is sharing the 2012 Nobel Prize in Chemistry with Brian K. Kobilka, M.D., of Stanford University School of Medicine, who was a post-doctoral fellow in Dr. Lefkowitz’s lab in the 1980s. The Nobel announcement of the prize was made on October 10, 2012. The two scientists are being recognized for their work on a class of cell surface receptors that have become the target of prescription drugs, including antihistamines, ulcer drugs, and beta blockers to relieve hypertension, angina, and coronary disease. The receptors receive chemical signals from the outside and transmit their messages into the cell, providing the cell with information about changes occurring within the body. These particular receptors are called seven-transmembrane G protein-coupled receptors, or just "G-coupled receptors" for short. Serpentine in appearance, G-coupled receptors weave through the surface of the cell seven times. The human genome contains code to make at least 1,000 different forms of these trans-membrane receptors, all of which are quite similar. The receptors also bear a strong resemblance to receptors that detect light in the eyes, smells in the nose, and taste on the tongue. "Bob's seminal discoveries related to G-protein coupled receptors ultimately became the basis for a great many medications that are in use today across many disease areas," said Victor J. Dzau, M.D., Chancellor for Health Affairs and CEO, Duke University Health System. "He is an outstanding example of a physician-scientist whose impact can be seen in the lives of the countless patients who have benefited from his scientific discoveries. We are very proud of his magnificent achievements and grateful for his many contributions to Duke Medicine." "We are thrilled that the Nobel Committee has recognized Bob's incredible body of work, and very proud that he has been on our faculty for his entire career" said Nancy Andrews, M.D., Ph.D., Dean, Duke University School of Medicine. "Bob is not just an extraordinary scientist but also a remarkable mentor; he has had a profound influence on the careers of more than 200 students and postdoctoral fellows." In addition to being one of the longest-serving Howard Hughes Medical Institute Investigators (HHMIs)in history (36 years), Lefkowitz is famous on the Duke campus for the attention he gives to mentoring his students. His lab has produced more than 200 graduate students and post-docs, including Dr. R. Sanders "Sandy" Williams, who later became his dean at Duke, and several researchers who went on to become HHMI investigators themselves. Dr. Lefkowitz is a professor of biochemistry, immunology and medicine, and also a basic research cardiologist in the Duke Heart Center. Among his students was Dr. Brian Kobilka, with whom he is sharing the Nobel Prize. Dr. Kobilka was a post-doctoral fellow in cardiology at Duke from 1984 to 1989 and part of Dr. Lefkowitz's lab. He joined the faculty of medicine and molecular and cellular physiology at Stanford in 1990. The two scientists will receive the Nobel Prize in Stockholm at a December 10, 2012 ceremony. "He's awesome," said Xiao Zhu, who just completed an undergrad degree at Duke after two years of independent study research in the Lefkowitz lab. "He's really receptive to having me in the lab and he's the brightest guy. He's very hands-on with checking in on what I'm up to." "Bob is the best mentor that he could be," said Dr. Arun Shukla, who was a post-doc and research scientist in the lab for six years before becoming an assistant professor at Duke. "Bob takes a great pride in training students and post-docs, and all of the big names in GPCR have come from his lab. He wants his students to have a tight focus on their research, but encourages them to ask really big questions.” Dr. Lefkowitz’s own scientific odyssey began in the early 1970s when he tried to develop a molecule that would bind to a specific receptor on the surface of a cell, which is like making a key for a lock that is too small to see. Trained as a cardiologist, Lefkowitz launched his quest by looking for adrenaline-sensitive receptors on the cell surface because he could use existing heart drugs that seemed to be acting on these receptors. Many senior scientists at that time doubted whether cell surface receptors for chemical signals even existed. Dr. Lefkowitz started by fixing the drugs to a solid surface and washing them in a slurry of ground-up cell membranes. Binding occurred between pieces of membrane and the molecules showing there was some affinity there. Still, skepticism prevailed. In the early 1980s, Lefkowitz’s lab incorporated a cell surface protein that attached to adrenaline into cells that wouldn't normally have responded to adrenaline. The cells acted as if they had adrenaline receptors. "That really did it for people. They realized we had it," Dr. Lefkowitz said. In the mid-1980s, the lab was able to clone the gene for the adrenaline receptor, which led them to the recognition of a familiar DNA motif and the rapid discovery of seven more, closely related receptors. This work opened up an entirely new area of pharmaceutical research. In subsequent years, the Lefkowitz group, which has included as many as 30 workers in the lab, found the G-protein-coupled receptor actually sets two chains of events in motion. It initiates signaling that cascades into the cell and prompts it to respond in an appropriate way. A second cascade is based on a feedback signal that leads to desensitization. A molecule called beta-arrestin binds to the G-coupled receptor and dampens its sensitivity or even turns it off temporarily. In recent years, Dr. Lefkowitz has been hard on the trail of a signaling molecule that will touch off the beta-arrestin signaling loop without triggering the G-protein signaling cascade. The result could be a “super blocker” that would do the heart-helping work of a beta blocker while also stimulating beneficial beta-arrestin signaling. "That's the nice thing about science," Dr. Lefkowitz said in a 2007 interview. "There's always a new detail to discover. It's like peeling an onion." [Duke press release] [Stanford press release] [Nobel press release]