Mechanisms of Cell Desensitization: Regulators of G protein Signaling

The Dohlman lab has for 25+ years invested in the education and training of new research scientists. We welcome individuals from diverse backgrounds, many of whom bring new perspectives to the research endeavor. Most of all we strive to promote a culture of cooperation and shared responsibility. In 2019 Dr. Dohlman was awarded the Office of Graduate Education Excellence in Basic Science Mentoring Award.

The lab’s research is centered on G proteins and G protein-coupled receptors (GPCRs). GPCRs respond to hormones and neurotransmitters, and are the target of one third of all pharmaceuticals. Generally speaking, persistent stimulation of these receptors leads 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. The lab has long 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 and characterization of the first RGS proteins (Dohlman et al. Mol Cell Biol 1995). RGS proteins inactivate G proteins by accelerating their intrinsic GTPase activity. Thus, RGS proteins work in opposition to GPCRs and serve as the molecular ‘brakes’ in cellular responses to neurotransmitters, environmental signals, and many pharmaceuticals.

Efforts in collaboration with Tim Elston‘s systems biology group seek to construct computational models of signaling networks and pathways; a 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.

Apart from RGS proteins, the lab has pioneered the use of mass spectrometry to map sites of ubiquitination (Marotti et al. Biochemistry 2002), demonstrated endomembrane signaling by G proteins (Slessareva, et al. Cell 2006), and showed that physiological changes in intracellular pH (Isom et al. Mol Cell 2013) as well as 2-hydroxy branched chain amino acids (Shellhammer et al. PLoS Genetics 2017) serve as second messengers of glucose limitation and osmotic stress, respectively. These novel second messengers share the ability to trigger G protein phosphorylation and dampen signaling. 2-hydroxy branched chain amino acids are elevated in patients with maple syrup urine disease and cause defects in neurotransmitter function.

 

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