Howard Hughes Medical Institute
Duke University Medical Center
Durham, North Carolina
LEFKOWITZ LAB
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     Our research program is concerned with the molecular properties and regulatory mechanisms that control the function of plasma membrane receptors for hormones and drugs under normal and pathological circumstances. Receptors are the cellular macromolecules with which biologically active substances (e.g., hormones, drugs, neurotransmitters, growth factors, viruses, lipoproteins) initially interact.

Description: /projects/2/5/6/2/2562115/images/f9f170863382a6a84ceea781bfefb107_1q3m.png     Some years ago we isolated the genes for all of the known adrenergic receptors, as well as a number of closely related receptors, and determined their complete amino acid sequences. The structure of the receptors consists of a polypeptide chain that weaves back and forth across the plasma membrane seven times ("seven-transmembrane-spanning receptors"). Remarkably, the structures of these receptors are similar to each other, to the visual light receptor rhodopsin, to the “smell receptors” in the nose, the taste receptors, opiate receptors, and hundreds of others. There appear to be about 1,000 such receptors encoded in the human genome that regulate virtually every known physiological process. Moreover, drugs that target these many receptors, either directly or indirectly, account for a substantial fraction of all prescription drug sales worldwide.


      One important insight to come from our studies of receptors is that their properties are not fixed. Rather, the properties of the receptors are influenced by the hormones and drugs with which they interact, as well as by a variety of disease states. There are important clinical implications of the ever-changing nature of the receptors. For example, this provides a basis for beginning to understand the phenomenon of drug tolerance, or desensitization, the diminishing effect of drugs over time. This phenomenon markedly compromises the therapeutic efficacy of epinephrine, opiates like morphine, and many other drugs. When drugs such as opiates combine with their receptors, they not only stimulate them but also produce changes that impair their function, thus leading to desensitization. As a result, cells are less able to respond to the drugs or hormones.

Our research has helped us to understand, in molecular terms, how the receptors become functionally desensitized. In this connection we have discovered two new families of proteins that function to desensitize the receptors. The first is a novel family of enzymes, the G protein–coupled receptor kinases (GRKs), that modify the structure of the receptors by introducing a phosphate group when the receptors are stimulated. The second is a group of proteins, the arrestins, that bind to the phosphorylated receptors and prevent them from acting. Both proteins are widely distributed, and their actions are not limited just to the β-adrenergic receptors.
Description: /projects/2/5/6/2/2562115/images/1c360f4a86f96b534142f2c89c6c4a98_1gu6_2ikk.png     Recently we discovered an entirely unexpected function of the β-arrestins and GRKs. Originally discovered and named for their ability to "desensitize" some functions of the receptors, the β-arrestins are also able to serve as signaling proteins in their own right. At the same time that they shut off G protein activation by the receptor, they also initiate a second wave of signaling to other pathways. We are just beginning to understand the consequences of this signalling.

     Understanding the actions of β-arrestins and GRKs may lead to the development of new drugs and new treatments for human diseases. For example, two of the most frequently used drugs for the treatment of heart and circulatory diseases are "β blockers" and "ARBs". "β Blockers" are β-adrenergic receptor blockers and ARBs are angiotensin receptor blockers. Both types of drugs work by binding to a seven transmembrane receptor (the β-adrenergic receptor for adrenaline or the angiotensin receptor respectively). In so doing they prevent the potentially deleterious effects of over stimulation of these receptors which can lead to hypertension, angina, or heart failure.

     However, the conventional blockers prevent all the actions of adrenaline or angiotension including some that may be beneficial. Until recently all the actions of these receptors were thought to be carried out by a single mechanism, the activation of a molecular switch called a "G protein". But now we know that some of their actions are carried out by activation of the β-arrestins. We have found that certain of these "β-arrestin-mediated" actions such as promoting cell survival and opposing cell death are potentially quite beneficial in the setting of cardiovascular and other diseases. Recently, we have found that it is possible to design drugs which, while blocking the potentially harmful effects of adrenaline or angiotensin mediated through G protein stimulation (like "conventional" blockers) are simultaneously able to stimulate potentially beneficial pathways mediated through β-arrestins.

Current efforts in the laboratory are directed at:

1. Developing biased ligands for several receptors.

2. Obtaining structural information about biased conformations of the β2-adrenergic  and angiotensin II 1A receptors using a variety of biophysical techniques including x-ray crystallography.

3. Exploring the physiological consequences of biased signaling for several GPCRs.

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