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

Author(s): Fitzgerald Kevin | Tertyshnikova Svetlana | Moore Lisa | Bjerke Lynn | Burley Ben | Cao Jian | Carroll Pamela | Choy Robert | Doberstein Steve | Dubaquie Yves | Franke Yvonne | Kopczynski Jenny | Korswagen Hendrik | Krystek Stanley R | Lodge Nicholas J | Plasterk Ronald | Starrett John | Stouch Terry | Thalody George | Wayne Honey | van der Linden Alexander | Zhang Yongmei | Walker Stephen G | Cockett Mark | Wardwell-Swanson Judi | Ross-Macdonald Petra | Kindt Rachel M

Journal: PLoS Genetics
ISSN 1553-7390

Volume: 2;
Issue: 4;
Start page: e57;
Date: 2006;
Original page

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-alphaq (G-protein alpha subunit). Our studies suggest that the small molecules act at the level of the RGS/G-alphaq signaling complex, and define new mutations in both RGS and G-alphaq, including a unique hypo-adapation allele of G-alphaq. These findings suggest that therapeutics targeted to downstream components of GPCR signaling may be effective for treatment of diseases involving inappropriate receptor activation.
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