Current Research

Robert Lefkowitz's 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.

Our research program is concerned with the molecular properties and regulatory mechanisms that control the function of plasma membrane receptors for hormones and drugs. Receptors are the cellular macromolecules with which biologically active substances (e.g., hormones, drugs, neurotransmitters, growth factors, viruses, lipoproteins) initially interact.

As models for the study of receptors, we have used primarily the receptors for epinephrine (adrenaline) and related compounds, which are generally termed adrenergic receptors, as well as the receptor for angiotensin 2, a powerful hormone that constricts blood vessels. Such receptors are found throughout the brain, heart, smooth muscle cells, and most other cells of the human organism. There are at least nine distinct subtypes of adrenergic receptors, which interact with endogenous epinephrine and norepinephrine and a variety of clinically important drugs.

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 receptors consist of a polypeptide chain that weaves back and forth across the plasma membrane seven times ("seven-transmembrane-spanning receptors"). Remarkably, the family of receptors that we thus discovered is now known to contain 1,000 different types of receptors. These include such diverse molecules as the visual light receptor rhodopsin, the smell receptors in the nose, the taste receptors for sweet and bitter, opiate receptors, and hundreds of others. Together they regulate virtually all known physiological processes. Moreover, drugs that target these many receptors account for a substantial fraction of all prescription drug sales.

One important insight from our studies of receptors is that their properties 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 understanding drug tolerance, or desensitization, the diminishing effect of drugs over time. This phenomenon markedly compromises the therapeutic efficacy of epinephrine, opiates such as morphine, and many other drugs. When such "agonists" 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 to understand, in molecular terms, how the receptors become desensitized. We discovered two 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 phosphate groups 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 appear to be universal for the family of seven transmembrane receptors.

Recently we discovered an unexpected function of the beta-arrestins and GRKs. Originally discovered and named for their ability to "desensitize" some functions of the receptors, the beta-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.

Understanding the actions of beta-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 beta blockers (beta-adrenergic receptor blockers) and ARBs (angiotensin receptor blockers). Both types of drugs work by binding to a seven-transmembrane-spanning receptor (the beta-adrenergic receptor for epinephrine or the angiotensin receptor, respectively). Thus they prevent the potentially deleterious effects of overstimulation of these receptors, which can lead to hypertension, angina, or heart failure. However, the conventional blockers prevent all the actions of epinephrine or angiotensin, 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 we now know that some of their actions are carried out by activation of the beta-arrestins. We have found that certain of these beta-arrestin-mediated actions, such as promoting cell survival and opposing cell death, are potentially beneficial in the setting of cardiovascular and other diseases.

Recently we have found that it is possible to design drugs that block the potentially harmful effects of epinephrine or angiotensin mediated through G protein stimulation (like "conventional" blockers) while at the same time stimulating potentially beneficial pathways mediated through beta-arrestins. We refer to such drugs as "biased" toward either G protein or beta-arrestin signaling. Two such drugs, derived from our work, are in phase 2 clinical trials. One is a beta-arrestin-biased agonist for the angiotensin receptor, which is being tested in patients with acute decompensated congestive heart failure. The other is a new form of opiate, a G protein-biased agonist for one of the opiate receptors, which is more potent than morphine, but appears to have fewer of the beta-arrestin-mediated side effects such as constipation, respiratory, depression, and tolerance.

X-ray crystal structure of a complex between activated β-arrestin 1...

A major focus of our current work is to establish the molecular basis for the ability of the receptors to independently stimulate signaling through either G proteins or beta-arrestins. This work involves the application of a variety of biophysical techniques, such as electron microscopy and x-ray crystallography, to the study of the conformations of the receptors, the beta-arrestins, and receptor-beta-arrestin complexes involved in these activities (Figure 1). It is hoped that eventually atomic-level information can be obtained from crystal structures of the different receptor and beta-arrestin conformations. Such work may aid in the design of ever more selective drugs with fewer and fewer side effects.

This work is supported in part by grants from the National Institutes of Health.

As of February 25, 2016

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