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Chemical Genetics Reveals an RGS/G-Protein Role in the Action of a Compound

Authors
  • 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
  • And 7 more
Publisher
Public Library of Science
Publication Date
Apr 01, 2006
Source
PMC
Keywords
Disciplines
  • Biology
  • Chemistry
  • Design
  • Medicine
License
Unknown

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.

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