- Regulators of G protein Signaling
Mechanisms of Cell Desensitization: Regulators of G protein Signaling.
Research in the Dohlman Lab is centered on G proteins and G protein-coupled receptors (GPCRs). GPCRs are the target of many pharmaceuticals, hormones and neurotransmitters, as well as most environmental signals. Generally speaking, persistent stimulation of G proteins lead to desensitization. Familiar examples include desensitization to light, odors and chemical stimulants such as caffeine.
Receptors, G proteins, and effector MAP kinases are conserved in evolution and are even found in the simplest eukaryotes such as yeast. Through large-scale genomics, proteomics and metabolomics analysis the lab has identified new mutants with altered signaling and desensitization properties. These are then characterized biochemically and biophysically using homologous proteins in humans. This approach led to the identification in yeast of a family of desensitization factors called RGS proteins (Regulator of G protein signaling). Whereas GPCRs activate G proteins, RGS proteins inactivate G proteins, by accelerating their GTPase activity.
Thus, RGS proteins serve as the molecular ‘brakes’ in cell signaling: they diminish our sensitivity to enviromental signals, neurotransmitters and pharmaceuticals over time.
Building on the RGS work, the lab is currently investigating how nutritional and stress signals, and their consequent molecular processes (e.g. feedback phosphorylation, protein ubiquitination, intracellular pH changes) can limit activation of competing signaling pathways. Efforts in collaboration with Tim Elston’s group seek to construct computational models of constituent signaling networks and pathways. The long-term objective is to devise predictive models of signal transduction in more complex systems, and ultimately determine how specific stimuli or drugs will influence the signaling network, in addition to specific target enzymes or receptors.