Regulator of G protein signaling (RGS) proteins speed GTP hydrolysis by Gi and Gq protein α-subunits. RGS2 is highly expressed in smooth muscle and selectively regulates Gαq signaling. RGS2 KO mice are hypertensive and show increased responses to angiotensin and α-adrenergic agonists. RGS2 mutations found in Japanese hypertensive patients reduce protein expression of RGS2 in cells. RGS2 is rapidly degraded, however, the exact mechanism is not known. The aim of this study was to use a high-throughput siRNA screen to identify genes that regulate protein expression of RGS2. RGS2 protein expression is up-regulated by the proteasome inhibitors MG-132 and Lactacystin in HEK-293T cells and in primary vascular smooth muscle cells. We utilized the DiscoveRx PathHunter™ ProLabel detection assay, a β-galactosidase complementation assay, that efficiently quantifies levels of proteins tagged with the 4kDa ProLabel tag. This assay was used to screen a druggable genome subset of the Dharmacon siGENOME SMART-POOL human siRNA library (~3,200 genes) which includes GPCRs, ion channels, kinases, and protein degradation genes. We identified several components of the ubiquitin protein degradation machinery whose knock-down increased RGS2 protein expression. Increased understanding of RGS2 protein regulation should help identify new RGS2 modulators for cardiovascular disease. (Supported by NIH-DA023252).