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

Fitzgerald K., Tertyshnikova S., Moore L., Bjerke L., Burley B., Cao J., Carroll P., Choy R., Doberstein S., Dubaquie Y., Franke Y., Kopczynski J., Korswagen H., Krystek S.R., Lodge N.J., Plasterk R., Starrett J., Stouch T., Thalody G., Wayne H., van der Linden A., Zhang Y., Walker S.G., Cockett M., Wardwell-Swanson J., Ross-Macdonald P., Kindt R.M.

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.

PLoS Genet. 2:e57-e57(2006) [PubMed] [Europe PMC]

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