Robert J. Lefkowitz

Robert J. Lefkowitz

James B. Duke Professor of Medicine and Biochemistry and Investigator, Howard Hughes Medical Institute

Isolation identification of neural receptor sites; interaction of neurotransmitters and receptors.

Contact Information

Office Number: (919) 684-2974

Fax: (919) 684-8875

e-mail lefko001@receptor-biol.duke.edu

Lab Location

Room 467 Carl Bldg

Mailing Address

467 Carl Bldg

Box 3821, DUMC

Durham, NC 27710

Education

Research Interests

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.

Keywords: Cell surface receptors, guanine nucleotide regulatory proteins, adenylyl cyclase, catacholamines, cardiac function, enzymes, drugs.

Selected Publications

1. Perry, S.J., Baillie, G.S., Kohout, T.A., McPhee, I., Magiera, M.M., Ang, K.L., Miller, W.E., McLean, A.J., Conti, M., Houslay, M.D. and Lefkowitz, R.J. Targeting of cyclic AMP degradation to b2-adrenergic receptors by b-arrestins. Science, 298:834-836, 2002. More…

2. Pierce, K.L., Premont, R.T. and Lefkowitz, R.J. Seven Transmembrane Spanning Receptors,Nature Rev. Molec. Cell. Biol. 3:639-650, 2002. More…

3. Zamah, A.M., Delahunty, M., Luttrell, L.M., Lefkowitz, R.J. PKA-Mediated Phosphorylation of the b2-Adrenergic Receptor Regulates it Coupling to Gs and Gi: Demonstration in a Reconstituted System. J. Biol. Chem. 277:31249-31256, 2002. More…

4. Shenoy, S.K., McDonald, P.H., Kohout, T.A., Lefkowitz, R.J. Agonist dependent ubiquitination of the b2Adrenergic Receptor and b-arrestin regulate receptor fate. Science, 294:1307-1313, 2001. More…

5. Luttrell, L.M., Roudabush, F.L., Choy, E.W., Miller, W.E., Field, M.E., Pierce, K.L., and Lefkowitz, R.J. Activation and targeting of extracellular signal-regulated kinases by barrestin scaffolds. Proc. Natl. Acad. Sci., USA, 98:2449-2454, 2001. More…

6. McDonald, P.H., Chow, C-W., Miller, W.E., Laporte, S.A., Field, M.E., Lin, F-T., Davis, R.J., and Lefkowitz, R.J. barrestin2: A receptor-regulated MAPK scaffold for the activation of JNK3. Science, 290:1574-1577, 2000. More…

7. Lefkowitz, R.J. The superfamily of heptahelical receptors. Nature Cell Biology 2:E132-E136, 2000. More…