Professor of Medicine
Professor of Biochemistry
Professor of Pathology
Professor of Chemistry
Associate of the Duke Initiative for Science & Society
Member of the Duke Cancer Institute
This laboratory focuses on elucidation of the molecular properties and regulatory mechanisms controlling the function of G protein-coupled receptors. The adrenergic receptors for adrenaline and related molecules are used as model systems.
The goal is to learn the general principles of signal transduction from the outside to the inside of the cell. These principles are involved in systems as diverse as sensory perception and neurotransmitter and hormonal signaling.
Studies are performed with isolated proteins, with whole cells in culture, and evenin 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 have isolated the enzymes and proteins involved in these processes and are 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 ß-arrestin. The same systems can also serve to transmit other signals from receptors. Most recently we have been developing lines of transgenic animals in which these various proteins are either over expressed or "knocked out" 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, especially in heart failure.
Quite recently, we have found that the β-arrestins, in addition to their ability to desensitize G protein signaling, are also able to signal in their own right to a variety of pathways, including:
- MAP kinases
- PI3 kinase
We have found ligands, for example, for the angiotensin receptor system, which are able to activate β-arrestin-mediated signaling while acting as an antagonist for G protein-mediated signaling. Such ligands may be prototypes for a whole new class of therapeutics, which might be called super-angiotensin receptor blockers or super-β-blockers by analogy. We are currently pursuing the development of such agents.
- Shah AS, White DC, Emani S, Kypson AP, Lilly E, Wilson K, Glower DD, Lefkowitz RJ, Koch, WJ. In vivo ventricular gene delivery of a ß-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction.Circulation 103:1311, 2001.
- Miller WE and Lefkowitz RJ. Expanding roles for ß-arrestins as scaffolds/adapters in GPCR signaling and trafficking. Current Opinion in Cell Biology 13:139, 2001.
- Harding VB, Jones, LR, Lefkowitz RJ, Koch WJ, Rockman HA. Cardiac ßARK1 inhibition prolongs survival and augments ß blocker therapy in a mouse model of severe heart failure. Proc Natl Acad Sci USA, 98:5809, 2001.
- Rockman HA. Cardiac ßARK1 inhibition prolongs survival and augments ß blocker therapy in a mouse model of severe heart failure. Proc Natl Acad Sci USA, 98:5809, 2001.
- Freeman K, Lerman I, Kranias EG, Bohlmeyer T, Bristow, MR, Lefkowitz, RJ, Iaccarino G, Koch WJ, Leinwand LA. Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy. J Clin Invest 107:967, 2001.
- Ahn S, Shenoy SK, Wei H, and Lefkowitz RJ. Differential kinetic and spatial patterns of b-arrestin2 and G protein-mediated ERK activated by the angiotensin II receptor. J Biol Chem. 279: 35518-35525, 2004.
- Lefkowitz RJ and Shenoy SK. Transduction of Receptor Signals by Beta-arrestins. Science 308: 512-517, 2005.
Robert J. Lefkowitz, MD, Director
Office: 467 Clinical and Research Labs, Durham, NC, 27710
Campus mail: DUMC Box 3821, Durham, NC, 27710
Phone: 919-684 2974