Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity.

Broadly, my research focuses on the role for G protein-coupled receptors in the pathophysiology of asthma. Asthma is a complex disease characterized by airway inflammation, hyperresponsiveness and remodeling. G protein-coupled receptors figure largely in the pathology and treatment of this disease. For example, beta-agonists, the rescue medication inhaled by asthmatics, act at airway smooth muscle beta2-adrenergic receptors (β2-AR) to relax the airways. However, excessive use of beta-agonists has been associated with clinical worsening of asthma control and increased mortality. β2-ARs can signal through two well characterized and independent signaling pathways; a G protein-dependent pathway and a beta-arrestin-dependent pathway. Previously we showed that mice lacking beta-arrestin-2 do not develop the symptoms of allergic airway inflammatory disease and that T cell and eosinophil migration to the lung is impaired in these mice. Similarly, others have shown that the asthma phenotype is significantly reduced in mice lacking global expression of β2-ARs. Thus, we hypothesize that the beta-arrestin-dependent signaling arm, downstream of the β2-AR, is responsible for promoting the asthma phenotype. The translational relevance of this work is high given that the determination of the signaling pathway that is utilized by β2-ARs can be influenced by the molecular signature of the agonist. Thus, our work could lead to the discovery of a β2-AR ligand that bronchodilates the airways without promoting asthma symptoms. In addition to transducing β2-AR-mediated signaling to promote asthma, we hypothesize that beta-arrestin-2 also mediates chemokine receptor signaling and thus, the inflammatory component of asthma. Chemokines, released in response to allergens, dictate the migration of immune cells to the lung in asthma and chemokine receptors are known to signal via both the G-dependent and beta-arrestin-dependent pathways.

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.