PLoS Genetics (Apr 2006)

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

  • Kevin Fitzgerald,
  • 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

DOI
https://doi.org/10.1371/journal.pgen.0020057
Journal volume & issue
Vol. 2, no. 4
p. e57

Abstract

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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.