Hetahelical receptor signaling: Beyond the G protein paradigm
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Hall, RA, RT Premont and RJ Lefkowitz (1999). Hetahelical receptor signaling: Beyond the G protein paradigm. Journal of Cell Biology, 145(5). pp. 927–932. 10.1083/jcb.145.5.927 Retrieved from https://hdl.handle.net/10161/7816.
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Critical physiological events throughout the body are controlled by extracellular signals from neurotransmitters and hormones acting on cell surface receptors. Receptors transduce these signals to alter intracellular metabolism and cellular responsiveness through heterotrimeric G protein/second messenger pathways or through small GTP-binding protein/protein kinase cascades.
The mechanisms that control the responsiveness of target organ G protein-coupled receptors include receptor phosphorylation and desensitization by G protein-coupled receptor kinases (GRKs). We have created mice lacking each of the three members of the GRK4 subfamily of GRKs (GRK4, GRK5 and GRK6), and are examining the functional effects of this loss of function on the physiology of receptors controlling gastrointestinal, heart, lung, immune and brain functions.
An important open question in the study of cellular regulation is understanding how cells coordinate the activity of multiple receptor pathways into a coherent cellular response. Our recent discovery that large multidomain ARF GTPase-activating proteins (GAPs) of the GIT family can serve as oligomeric scaffolding proteins for numerous signaling molecules and help coordinate heterotrimeric G protein and multiple small GTP-binding protein pathways, suggests that other multidomain ARF GAPs may also function in analogous manner as coordination centers. We are examining the functional roles of GIT proteins and related ARF GAPs in crosstalk among cellular signaling pathways, with particular emphasis on gastrointestinal and behavioral roles using GIT1 and GIT2 knockout mice.
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his early career as a cardiologist and his transition to biochemistry, which led to his Nobel Prize win.
Robert J. Lefkowitz, M.D. is Chancellor’s Distinguished Professor of Medicine and Professor of Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator of the Howard Hughes Medical Institute since 1976. Dr. Lefkowitz began his research career in the late 1960’s and early 1970’s when there was not a clear consensus that specific receptors for drugs and hormones even existed. His group spent 15 difficult years developing techniques for labeling the receptors with radioactive drugs and then purifying the four different receptors that were known and thought to exist for adrenaline, so called adrenergic receptors. In 1986 Dr. Lefkowitz transformed the understanding of what had by then become known as G protein coupled receptors because of the way the receptor signal for the inside of a cell through G proteins, when he and his colleagues cloned the gene for the beta2-adrenergic receptor. They immediately recognized the similarity to a molecule called rhodopsin which is essentially a light receptor in the retina. This unexpected finding established the beta receptor and rhodopsin as the first member of a new family of proteins. Because each has a peptide structure, which weaves across the cell membrane seven times, these receptors are referred to as seven transmembrane receptors. This super family is now known to be the largest, most diverse and most therapeutically accessible of all the different kinds of cellular receptors. There are almost a thousand members of this receptor family and they regulate virtually all known physiological processes in humans. They include the receptors not only to numerous hormones and neurotransmitters but for the receptors which mediate the senses of sweet and bitter taste and smell amongst many others. Dr. Lefkowitz also discovered the mechanism by which receptor signaling is turned off, a process known as desensitization. Dr. Lefkowitz work was performed at the most fundamental and basic end of the research spectrum and has had remarkable consequences for clinical medicine. Today, more than half of all prescription drug sales are of drugs that target either directly or indirectly the receptors discovered by Dr. Lefkowitz and his trainees. These include amongst many others beta blockers, angiotensin receptor blockers or ARBs and antihistamines. Over the past decade he has discovered novel mechanisms by which the receptors function which may lead to the development of an entirely new class of drugs called “biased agonists”. Several such compounds are already in advanced stages of clinical testing. Dr. Lefkowitz has received numerous honors and awards, including the National Medal of Science, the Shaw Prize, the Albany Prize, and the 2012 Nobel Prize in Chemistry. He was elected to the USA National Academy of Sciences in 1988, the Institute of Medicine in 1994, and the American Academy of Arts and Sciences in 1988.
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