{"id":2234,"date":"2017-06-08T20:45:00","date_gmt":"2017-06-09T00:45:00","guid":{"rendered":"https:\/\/www.med.unc.edu\/pharm\/dohlmanlab\/research\/"},"modified":"2026-02-20T10:13:51","modified_gmt":"2026-02-20T15:13:51","slug":"research","status":"publish","type":"page","link":"https:\/\/www.med.unc.edu\/pharm\/dohlmanlab\/research\/","title":{"rendered":"Our Research"},"content":{"rendered":"

Mechanisms of Cell Desensitization: Regulators of G protein Signaling<\/h3>\n

Research in the\u00a0Dohlman Lab\u00a0is focused on\u00a0G proteins\u00a0and\u00a0G protein-coupled receptors\u00a0(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\u00a0include desensitization to light, odors and drugs of abuse, including opioids.<\/p>\n

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<\/em> 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.<\/p>\n

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 \u03b1 subunit, and how these states differ among the four major subclasses of G\u03b1 subtypes. Following a systematic analysis of mutations in G\u03b1o<\/sub>, 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.<\/p>\n

SELECTED PUBLICATIONS<\/p>\n