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 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.
Fitzgerald
Kevin
K
Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, New Jersey, United States of America.
Tertyshnikova
Svetlana
S
Moore
Lisa
L
Bjerke
Lynn
L
Burley
Ben
B
Cao
Jian
J
Carroll
Pamela
P
Choy
Robert
R
Doberstein
Steve
S
Dubaquie
Yves
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Franke
Yvonne
Y
Kopczynski
Jenny
J
Korswagen
Hendrik
H
Krystek
Stanley R
SR
Lodge
Nicholas J
NJ
Plasterk
Ronald
R
Starrett
John
J
Stouch
Terry
T
Thalody
George
G
Wayne
Honey
H
van der Linden
Alexander
A
Zhang
Yongmei
Y
Walker
Stephen G
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Cockett
Mark
M
Wardwell-Swanson
Judi
J
Ross-Macdonald
Petra
P
Kindt
Rachel M
RM