Master of Science
Physiology and Pharmacology
Regulator of G protein signaling protein 2 (RGS2) attenuates G Protein-Coupled Receptor (GPCR) signaling by promoting the hydrolysis of GTP in the activated Gα subunit to GDP, thereby governing many physiological and pathophysiological signals. However, how RGS2 itself is regulated remains to be elucidated. In this study, our principal goal was to discover the molecular mechanisms controlling RGS2 degradation and if altered degradation affects Gα signaling. RGS2 has four initiation sites (at residues 1, 5, 16, and 33), resulting in the existence of four distinct N-terminal initiation site variants. Additionally, there are naturally occurring mutations in this region at residues 5 (RGS2 M5V), 14 (RGS2 R14I), 18 (RGS2 K18N) and 23 (RGS2 G23D), which may be associated with a phenotypic profile seen in individuals with the mutant forms. Here we report that the use of each initiator methionine residue, as well as mutations within the N-terminus of RGS2, can have profound effects on RGS2 half-life. Additionally, we show a correlation between RGS2 half-life and the ability to attenuate Gαq/11 signaling. Finally, we provide evidence that RGS2 is degraded via the ubiquitin-proteasome pathway. Considering the importance of RGS2 in pathophysiological conditions, altered degradation associated with initiation variants or mutant isoforms could be contributing to such conditions.
Stockwell, Patrick, "Stability and Activity of Naturally Occurring RGS2 Variants" (2015). Electronic Thesis and Dissertation Repository. 3004.