I. Seven Transmembrane Receptors
Part I: Seven Transmembrane Receptors
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In the first segment of the lecture, the history of discovery in the field of seven transmembrane receptor research over the past forty years is reviewed. Highlights include overcoming initial skepticism that the receptors even existed; isolating the receptors as discrete biochemical entities and demonstrating their ligand binding and functional activating properties; discovering their seven transmembrane spanning arrangement and homology with the visual light receptor rhodopsin, thereby leading to the discovery of the wider seven transmembrane receptor superfamily; determination of the structure – function relationships of the receptors by mutagenesis and chimeric receptor construction; discovery of constitutively active mutant receptors; discovery of the phosphorylation of the receptors by G protein coupled receptor kinases, and of the beta-arrestins and of their universal mechanism for desensitizing the receptors.
In part 2 of the lecture, recent discoveries about how beta-arrestins not only desensitize the receptors but also mediate their endocytosis, as well as independent signaling pathways, are reviewed. Also covered is how these new discoveries provide a basis for designing novel classes of pharmacological agents which can promote signaling exclusively down either the G protein or beta-arrestin mediated pathways, so called “biased” agonists.
Dr. Lefkowitz is an Investigator of the Howard Hughes Medical Institute, Professor of Medicine, and Professor of Biochemistry and Immunology at Duke University Medical Center. Lefkowitz was an undergraduate at Columbia College and received his M.D. Degree from Columbia University College of Physicians and Surgeons. He completed his medical, research and clinical training in cardiovascular disease at the National Institutes of Health and Massachusetts General Hospital.
Lefkowitz moved to Duke University in 1973 and has remained there since. His research has focused on the molecular structure and regulatory mechanisms controlling the function of the seven transmembrane family of receptors. Lefkowitz is a member of the National Academy of Sciences, the Institute of Medicine and the American Academy of Arts and Sciences. In 2012, Lefkowitz was awarded the Nobel Prize in Chemistry in recognition of his seminal contributions to understanding G protein coupled receptors.
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Lefkowitz, R.J. The superfamily of heptahelical receptors. Nature Cell Biology 2:E132-E136, 2000.
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Lefkowitz, R.J. Seven transmembrane receptors: something old, something new. Acta Physiologica 190:9-19, 2007.
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Lefkowitz, R.J., Rajagopal, K. and Whalen, E.J. New Roles for β-Arrestins in Cell Signaling: Not Just for Seven Transmembrane Receptors. Molecular Cell 24:643-652, 2006.