- Regulators of G protein Signaling
Mechanisms of Cell Desensitization: Regulators of G protein Signaling.
Our research is centered on G proteins and G protein-coupled receptors (GPCRs). GPCRs are the target of nearly half of all pharmaceuticals, as well as light, taste, odors, hormones and neurotransmitters. 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. We have been conducting large-scale genomic and proteomic analysis in yeast to identify mutants with altered signaling and desensitization properties. These mutants are then characterized biochemically in yeast as well as in animal cells using homologous components. This approach led to the identification in yeast of a family of desensitization factors called RGS proteins (Regulator of G protein signaling). RGS proteins inactivate G proteins by accelerating their intrinsic 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, we are currently investigating how other regulatory processes (e.g. feedback phosphorylation, protein ubiquitination, intracellular pH changes) can limit activation of competing parallel 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.