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

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 t...

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Main Authors:	Fitzgerald, Kevin, Tertyshnikova, Svetlana, Moore, Lisa, Bjerke, Lynn, Burley, Ben, Cao, Jian, Carroll, Pamela, Choy, Robert, Doberstein, Steve, Dubaquie, Yves, Franke, Yvonne, Kopczynski, Jenny, Korswagen, Hendrik, Krystek, Stanley R, Lodge, Nicholas J, Plasterk, Ronald, Starrett, John, Stouch, Terry, Thalody, George, Wayne, Honey, van der Linden, Alexander, Zhang, Yongmei, Walker, Stephen G, Cockett, Mark, Wardwell-Swanson, Judi, Ross-Macdonald, Petra, Kindt, Rachel M
Format:	Online
Language:	English
Published:	Public Library of Science 2006
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1440875/

id	pubmed-1440875
recordtype	oai_dc
spelling	pubmed-14408752006-05-08 Chemical Genetics Reveals an RGS/G-Protein Role in the Action of a Compound Fitzgerald, Kevin Tertyshnikova, Svetlana Moore, Lisa Bjerke, Lynn Burley, Ben Cao, Jian Carroll, Pamela Choy, Robert Doberstein, Steve Dubaquie, Yves Franke, Yvonne Kopczynski, Jenny Korswagen, Hendrik Krystek, Stanley R Lodge, Nicholas J Plasterk, Ronald Starrett, John Stouch, Terry Thalody, George Wayne, Honey van der Linden, Alexander Zhang, Yongmei Walker, Stephen G Cockett, Mark Wardwell-Swanson, Judi Ross-Macdonald, Petra Kindt, Rachel M Research Article 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. Public Library of Science 2006-04 2006-04-21 /pmc/articles/PMC1440875/ /pubmed/16683034 http://dx.doi.org/10.1371/journal.pgen.0020057 Text en © 2006 Fitzgerald et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Fitzgerald, Kevin Tertyshnikova, Svetlana Moore, Lisa Bjerke, Lynn Burley, Ben Cao, Jian Carroll, Pamela Choy, Robert Doberstein, Steve Dubaquie, Yves Franke, Yvonne Kopczynski, Jenny Korswagen, Hendrik Krystek, Stanley R Lodge, Nicholas J Plasterk, Ronald Starrett, John Stouch, Terry Thalody, George Wayne, Honey van der Linden, Alexander Zhang, Yongmei Walker, Stephen G Cockett, Mark Wardwell-Swanson, Judi Ross-Macdonald, Petra Kindt, Rachel M
spellingShingle	Fitzgerald, Kevin Tertyshnikova, Svetlana Moore, Lisa Bjerke, Lynn Burley, Ben Cao, Jian Carroll, Pamela Choy, Robert Doberstein, Steve Dubaquie, Yves Franke, Yvonne Kopczynski, Jenny Korswagen, Hendrik Krystek, Stanley R Lodge, Nicholas J Plasterk, Ronald Starrett, John Stouch, Terry Thalody, George Wayne, Honey van der Linden, Alexander Zhang, Yongmei Walker, Stephen G Cockett, Mark Wardwell-Swanson, Judi Ross-Macdonald, Petra Kindt, Rachel M Chemical Genetics Reveals an RGS/G-Protein Role in the Action of a Compound
author_facet	Fitzgerald, Kevin Tertyshnikova, Svetlana Moore, Lisa Bjerke, Lynn Burley, Ben Cao, Jian Carroll, Pamela Choy, Robert Doberstein, Steve Dubaquie, Yves Franke, Yvonne Kopczynski, Jenny Korswagen, Hendrik Krystek, Stanley R Lodge, Nicholas J Plasterk, Ronald Starrett, John Stouch, Terry Thalody, George Wayne, Honey van der Linden, Alexander Zhang, Yongmei Walker, Stephen G Cockett, Mark Wardwell-Swanson, Judi Ross-Macdonald, Petra Kindt, Rachel M
author_sort	Fitzgerald, Kevin
title	Chemical Genetics Reveals an RGS/G-Protein Role in the Action of a Compound
title_short	Chemical Genetics Reveals an RGS/G-Protein Role in the Action of a Compound
title_full	Chemical Genetics Reveals an RGS/G-Protein Role in the Action of a Compound
title_fullStr	Chemical Genetics Reveals an RGS/G-Protein Role in the Action of a Compound
title_full_unstemmed	Chemical Genetics Reveals an RGS/G-Protein Role in the Action of a Compound
title_sort	chemical genetics reveals an rgs/g-protein role in the action of a compound
description	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.
publisher	Public Library of Science
publishDate	2006
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1440875/
_version_	1611381999253061632

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

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