Chemical genetics reveals an RGS/G-protein role in the action of a compound.

We report here on a chemical genetic screen designed to address the mechanism of action of a small molecule. Small molecules that were active in models of urinary incontinence were tested on the nematode Caenorhabditis elegans, and the resulting phenotypes were used as readouts in a genetic screen to identify possible molecular targets. The mutations giving resistance to compound were found to affect members of the RGS protein/G-protein complex. Studies in mammalian systems confirmed that the small molecules inhibit muscarinic G- protein coupled receptor (GPCR) signaling involving G-alpha q (G- protein alpha subunit). Our studies suggest that the small molecules act at the level of the RGS/G-alpha q signaling complex, and define new mutations in both RGS and G-alpha q, including a unique hypo-adapation allele of G-alpha q. These findings suggest that therapeutics targeted to downstream components of GPCR signaling may be effective for treatment of diseases involving inappropriate receptor activation.