Thomas J. Baranski, M.D., Ph.D.

DEPARTMENT OF Internal Medicine
Keywords: signal transduction, receptor, G protein, hormone, protein structure

Our laboratory studies signal transduction by G protein-coupled receptors, a superfamily of heptahelical transmembrane proteins. The receptors act as elegantly engineered switches, receiving signals involved in many physiologic processes — blood pressure regulation, glucose homeostasis, sight and smell — to turn on specific signaling cascades within cells. Remarkably, we devote more than 3 percent of our entire genome to encoding these receptors. Despite their widespread importance, we do not understand how the receptors actually function as ligand-activated switches.

We use engineered yeast to apply the power of genetics to the study of signaling by human G protein-coupled receptors. In one strategy, we use saturation mutagenesis to force segments of a chemoattractant receptor to evolve at an extremely high rate. We have generated the largest set of functional mutations within any G protein-coupled receptor. Combined with bioinformatic approaches, this data allows us to build higher-resolution models of the receptor structure. Insights into how ligands activate receptors will aid in drug design and greatly impact medicine; more than half of currently prescribed pharmaceuticals target G protein-coupled receptors.

Our future goals include identifying mechanisms that govern the specificity and efficiency of receptor signaling in cells. We use a variety of techniques including fluorescence microscopy, cellular fractionation and biochemical reconstitution assays to characterize the cell biology of receptor signaling. We believe that G protein-coupled receptors serve as an important cornerstone to understanding the intricate and complex mechanisms of signal transduction in cells.