We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Chemical Genetics Reveals an RGS/G-Protein<br /> Role in the Action of a Compound.
- Authors
Fitzgerald, Kevin; Tertyshnikova, Svetlana; Moore, Lisa; Bjerke, Lynn; Burley, Ben; Jian Cao; Carroll, Pamela; Choy, Robert; Doberstein, Steve; Dubaquie, Yves; Franke, Yvonne; Kopczynski, Jenny; Korswagen, Hendrik; Krystek Jr., Stanley R.; Lodge, Nicholas J.; Plasterk, Ronald; Starrett, John; Stouch, Terry; Thalody, George; Wayne, Honey
- Abstract
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-αq (G-protein alpha subunit). Our studies suggest that the small molecules act at the level of the RGS/G-αq signaling complex, and define new mutations in both RGS and G-αq, including a unique hypo-adapation allele of G-αq. These findings suggest that therapeutics targeted to downstream components of GPCR signaling may be effective for treatment of diseases involving inappropriate receptor activation.
- Subjects
BIOCHEMICAL genetics; URINARY incontinence; CAENORHABDITIS elegans; NEMATODES; G proteins; GENETIC mutation
- Publication
PLoS Genetics, 2006, Vol 2, Issue 4, pe57
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.0020057