1970’s-1980’s: Discovery of the GPCR superfamily and its classic seven membrane spanning domain organization. GPCRs are now known to constitute almost 1,000 genes in humans and to provide the commonest targets for therapeutic drugs. 

1980’s-1990’s: Discovery of how GPCR signaling is regulated by the G protein-coupled receptor kinases (GRKs) and β-arrestins. The two protein families that we discovered desensitize GPCRs and also mediate their internalization through a highly conserved mechanism. 

1990’s-2000’s: Discovery of non-G protein-mediated GPCR signaling. We discovered that the β-arrestin/GRK system not only desensitizes classical, G protein-mediated GPCR signaling but also constitutes a signal transduction system in its own right. 

2000’s: Discovery of “biased” GPCR signaling. We discovered that certain GPCR ligands can selectively activate either G protein- or β-arrestin-mediated signaling, a phenomenon variously known as biased agonism, functional selectivity or ligand-directed signaling. This principle could be used to design “biased” drugs with greater specificity of action and fewer side effects targeting any number of GPCRs. The first such drugs have progressed to clinical trials.


For more than forty years my laboratory has studied the molecular and regulatory properties of G protein-coupled receptors (GPCRs), also known as seven transmembrane spanning receptors (7TMRs). This is by far the largest most versatile and ubiquitous of the several plasma membrane families of receptors. Our laboratory has made a number of major contributions to the understanding of GPCR function:

​​Current work in the lab focuses on understanding how GPCR cell signaling, by biased or unbiased ligands, is mediated through GPCRs and their transducers, the G proteins and the β-arrestins. As model systems, we use two receptors of great cardiovascular significance, the β2-adrenergic receptor and the angiotensin II type 1 receptor. Techniques employed range from biophysics to pharmacology to cell biology to in vivo animal disease models. A recent focus has been on dissecting the molecular mechanisms by which biased signaling is generated with an emphasis on GPCR – β-arrestin interactions.

Recent progress includes: 

1) The structure of β-arrestin1 in its activated conformation. The 2.6 Å X-ray crystal structure of β-arrestin1 in complex with a phosphopeptide mimic of a GPCR C-terminus stabilized by an antigen binding fragment (Figure 1).

Nature 2013, 497(7447):137-141. http://www.ncbi.nlm.nih.gov/pubmed/23604254

2) Biophysical analysis of a chimeric β2-adrenergic receptor in complex with β-arrestin1. The architecture of this complex, stabilized by an antigen binding fragment, was delineated by single particle analysis and 3D reconstruction of negative stain EM images, hydrogen deuterium exchange, lysine crosslinking, and disulfide trapping (Figure 2). 

Nature 2014, 512(7513):218-222. http://www.ncbi.nlm.nih.gov/pubmed/25043026

3) Development of methods to accurately quantify GPCR ligands’ bias in vitro. We used fusion proteins of the angiotensin receptor to its transducers (G protein and β-arrestin2) in conjunction with radioligand binding assays to evaluate how well biased and unbiased ligands promote coupling of the receptor to each transducer. This allows ligand bias to be measured without the complexities of cell-based signaling assays. 

J Biol Chem 2014, 289(20):14211-14224. http://www.ncbi.nlm.nih.gov/pubmed/24668815

In other projects we are identifying novel allosteric ligands for GPCRs using a variety of innovative approaches.  These allosteric ligands, while having therapeutic import in their own right, are also utilized to stabilize novel conformations of the receptors to dissect their pharmacology and structure. Several other projects involve studying the impact of genetic deletion of β-arrestins on the course of hematological malignanci
es and aortic aneurysms.