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
  • 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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