Robert J. Lefkowitz, MD

Professor of Medicine
James B. Duke Professor of Medicine
Professor of Biochemistry
Professor of Pathology
Professor of Chemistry
Member of the Duke Cancer Institute
Campus mail 467 Clin & Res Labs, Durham, NC 27710
Phone (919) 684-2974
Email address lefko001@receptor-biol.duke.edu

The focus of work in this laboratory is on the elucidation of the molecular properties and regulatory mechanisms controlling the function of G protein-coupled receptors. As model systems we utilize the so called adrenergic receptors for adrenaline and related molecules. The goal is to learn the general principles of signal transduction from the outside to the inside of the cell which are involved in systems as diverse as sensory perception, neuro- transmitter and hormonal signaling. Studies are performed with isolated protein, whole cells in culture and even in vivo in whole animals.

Current projects emphasize attempts to understand regulation of the receptors and their desensitization which occurs in response to persistent stimulation. We are isolating the enzymes and proteins involved in these processes and studying their mechanisms of action in isolated protein and cellular systems as well as in whole animals. Most important are special enzymes called G protein-coupled receptor kinases which phosphorylate the receptors and lead to their desensitization which occurs when they bind a second protein called barrestin. Most recently we have been developing lines of transgenic animals in which these various proteins are either overexpressed or "knockedout" by homologous recombination. These genetically altered animal lines are helping to shed new light on the ways in which receptors are regulated. They also have suggested several novel approaches to human therapeutics.

While no clinical trials are currently in progress in our program we are experimenting with novel approaches to the treatment of congestive heart failure in animal models. Specifically we are injecting recombinant adenovirus encoding either the b-adrenergic receptors or inhibitors of the b-adrenergic receptor kinase down the coronary arteries of rabbits. The hope is that these gene products when expressed in the myocardium will markedly enhance cardiac contractility.

Dr. Lefkowitz has received a great deal of recognition for his research including election to the National Academy of Sciences and the Institute of Medicine of the National Academy of Sciences as well as the receipt of numerous awards. Most recently these have included the The Louis and Artur Lucian Award for Research in Circulatory Disease, The Fred Conrad Koch Award - The Endocrine Society, The 2001 Jessie Stevenson Kovalenko Medal - The National Academy of Sciences and The Peter Harris Distinguished Scientist Award, International Society of Heart Research. Dr. Lefkowitz writes numerous review articles in the areas of hormone and drug receptors and their regulation and is a consultant for several drug companies which specialize in drugs which may affect signal transduction processes such as Norak, Lexicon Genetics and Genentech.

Education and Training

  • M.D., Columbia University, 1966

Publications

Shukla, AK, Sun, J-P, and Lefkowitz, RJ. "Crystallizing thinking about the beta2-adrenergic receptor." Mol Pharmacol 73, no. 5 (May 2008): 1333-1338.

PMID
18239031
Full Text

DeWire, SM, Kim, J, Whalen, EJ, Ahn, S, Chen, M, and Lefkowitz, RJ. "Beta-arrestin-mediated signaling regulates protein synthesis." J Biol Chem 283, no. 16 (April 18, 2008): 10611-10620.

PMID
18276584
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Lefkowitz, RJ. "The annual ASCI meeting: does nostalgia have a future?." J Clin Invest 118, no. 4 (April 2008): 1231-1233.

PMID
18382732
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Drake, MT, Violin, JD, Whalen, EJ, Wisler, JW, Shenoy, SK, and Lefkowitz, RJ. "beta-arrestin-biased agonism at the beta2-adrenergic receptor." J Biol Chem 283, no. 9 (February 29, 2008): 5669-5676.

PMID
18086673
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Violin, JD, DiPilato, LM, Yildirim, N, Elston, TC, Zhang, J, and Lefkowitz, RJ. "beta2-adrenergic receptor signaling and desensitization elucidated by quantitative modeling of real time cAMP dynamics." J Biol Chem 283, no. 5 (February 1, 2008): 2949-2961.

PMID
18045878
Full Text

Violin, JD, DiPilato, LM, Yildirim, N, Elston, TC, Zhang, J, and Lefkowitz, RJ. "β2-Adrenergic receptor signaling and desensitization elucidated by quantitative modeling of real time cAMP dynamics." Journal of Biological Chemistry 283, no. 5 (February 1, 2008): 2949-2961.

Full Text

Lefkowitz, RJ, Sun, J-P, and Shukla, AK. "A crystal clear view of the beta2-adrenergic receptor." Nat Biotechnol 26, no. 2 (February 2008): 189-191.

PMID
18259173
Full Text

Beaulieu, J-M, Marion, S, Rodriguiz, RM, Medvedev, IO, Sotnikova, TD, Ghisi, V, Wetsel, WC, Lefkowitz, RJ, Gainetdinov, RR, and Caron, MG. "A beta-arrestin 2 signaling complex mediates lithium action on behavior." Cell 132, no. 1 (January 11, 2008): 125-136.

PMID
18191226
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Beaulieu, J-M, Marion, S, Rodriguiz, RM, Medvedev, IO, Sotnikova, TD, Ghisi, V, Wetsel, WC, Lefkowitz, RJ, Gainetdinov, RR, and Caron, MG. "A beta-arrestin 2 signaling complex mediates lithium action on Behavior." CELL 132, no. 1 (January 11, 2008): 125-136.

Full Text

Wisler, JW, DeWire, SM, Whalen, EJ, Violin, JD, Drake, MT, Ahn, S, Shenoy, SK, and Lefkowitz, RJ. "A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling." Proc Natl Acad Sci U S A 104, no. 42 (October 16, 2007): 16657-16662.

PMID
17925438
Full Text

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