PhD
Sanford Steelman Distinguished Professor and Chair, Pharmacology
Biochemistry and Biophysics
UNC-Chapel Hill
Cancer Cell Biology Research Program
Area of Interest
Research in the Dohlman Lab is focused on G proteins and G protein-coupled receptors (GPCRs). These receptors are the target for two-thirds of hormones and neurotransmitters, many pharmaceuticals, and most environmental signals. Generally speaking, persistent stimulation of G proteins leads to desensitization. Familiar examples include desensitization to light, odors and drugs of abuse, including opioids. The research strategy relies on large-scale genomic, proteomic, and metabolomic analysis to identify G protein variants with altered signaling and desensitization properties. Mutants are then characterized biochemically and in cells. This effort led to the identification of the first RGS protein, which inactivates G proteins by accelerating their intrinsic GTPase activity. The lab was also the first to use mass spectrometry to map a site of protein ubiquitination in vivo, and the first to demonstrate signaling by G proteins at internal cellular compartments. Mutations in G proteins are responsible for disease; the best-known examples are uveal melanoma and developmental epileptic encephalopathies. The lab is currently investigating how these disease mutations impose an ensemble of conformational states on the G protein α subunit, and how these states differ among the four major subclasses of Gα subtypes. Following a systematic analysis of mutations in Gαo, all linked to epileptic encephalopathies, the lab identified several that block or lock key steps of the G protein activation cycle. Most of the mutations act at a distance, by imposing or disrupting important allosteric communication networks. These studies are revealing new ways by which G proteins are activated and desensitized. In the longer term it is likely that specific conformational states can be imposed by using existing approved drugs that target GPCRs.
