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

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

  • PLoS Genet. 2006 Apr;2(4):e57. doi: 10.1371/journal.pgen.0020057.
Kevin Fitzgerald 1,  Svetlana Tertyshnikova,  Lisa Moore,  Lynn Bjerke,  Ben Burley,  Jian Cao,  Pamela Carroll,  Robert Choy,  Steve Doberstein,  Yves Dubaquie,  Yvonne Franke,  Jenny Kopczynski,  Hendrik Korswagen,  Stanley R Krystek,  Nicholas J Lodge,  Ronald Plasterk,  John Starrett,  Terry Stouch,  George Thalody,  Honey Wayne,  Alexander van der Linden,  Yongmei Zhang,  Stephen G Walker,  Mark Cockett,  Judi Wardwell-Swanson,  Petra Ross-Macdonald,  Rachel M Kindt
Affiliations

Affiliation

  • 1 Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, New Jersey, United States of America.
PMID: 16683034 DOI: 10.1371/journal.pgen.0020057
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-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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