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• W3133201734 abstract "Heterotrimeric G protein subunits Gαq and Gα11 are inhibited by two cyclic depsipeptides, FR900359 (FR) and YM-254890 (YM), both of which are being used widely to implicate Gq/11 proteins in the regulation of diverse biological processes. An emerging major research question therefore is whether the cellular effects of both inhibitors are on-target, that is, mediated via specific inhibition of Gq/11 proteins, or off-target, that is, the result of nonspecific interactions with other proteins. Here we introduce a versatile experimental strategy to discriminate between these possibilities. We developed a Gαq variant with preserved catalytic activity, but refractory to FR/YM inhibition. A minimum of two amino acid changes were required and sufficient to achieve complete inhibitor resistance. We characterized the novel mutant in HEK293 cells depleted by CRISPR–Cas9 of endogenous Gαq and Gα11 to ensure precise control over the Gα-dependent cellular signaling route. Using a battery of cellular outcomes with known and concealed Gq contribution, we found that FR/YM specifically inhibited cellular signals after Gαq introduction via transient transfection. Conversely, both inhibitors were inert across all assays in cells expressing the drug-resistant variant. These findings eliminate the possibility that inhibition of non-Gq proteins contributes to the cellular effects of the two depsipeptides. We conclude that combined application of FR or YM along with the drug-resistant Gαq variant is a powerful in vitro strategy to discern on-target Gq against off-target non-Gq action. Consequently, it should be of high value for uncovering Gq input to complex biological processes with high accuracy and the requisite specificity. Heterotrimeric G protein subunits Gαq and Gα11 are inhibited by two cyclic depsipeptides, FR900359 (FR) and YM-254890 (YM), both of which are being used widely to implicate Gq/11 proteins in the regulation of diverse biological processes. An emerging major research question therefore is whether the cellular effects of both inhibitors are on-target, that is, mediated via specific inhibition of Gq/11 proteins, or off-target, that is, the result of nonspecific interactions with other proteins. Here we introduce a versatile experimental strategy to discriminate between these possibilities. We developed a Gαq variant with preserved catalytic activity, but refractory to FR/YM inhibition. A minimum of two amino acid changes were required and sufficient to achieve complete inhibitor resistance. We characterized the novel mutant in HEK293 cells depleted by CRISPR–Cas9 of endogenous Gαq and Gα11 to ensure precise control over the Gα-dependent cellular signaling route. Using a battery of cellular outcomes with known and concealed Gq contribution, we found that FR/YM specifically inhibited cellular signals after Gαq introduction via transient transfection. Conversely, both inhibitors were inert across all assays in cells expressing the drug-resistant variant. These findings eliminate the possibility that inhibition of non-Gq proteins contributes to the cellular effects of the two depsipeptides. We conclude that combined application of FR or YM along with the drug-resistant Gαq variant is a powerful in vitro strategy to discern on-target Gq against off-target non-Gq action. Consequently, it should be of high value for uncovering Gq input to complex biological processes with high accuracy and the requisite specificity. Heterotrimeric αβγ guanine nucleotide-binding proteins (G proteins) are the main transducers of G protein–coupled receptors (GPCRs), the largest family of membrane proteins in mammalian cells (1Gilman A.G. 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G proteins mainly relay chemical and physical information from GPCRs to the cell interior to regulate numerous intracellular responses. In this manner, the GPCR–G protein–signaling cascade contributes to an amazing repertoire of physiological and pathophysiological events that are relevant for the regulation of blood pressure, cell proliferation, and metabolism, among many other vital functions (7Wettschureck N. Offermanns S. Mammalian G proteins and their cell type specific functions.Physiol. Rev. 2005; 85: 1159-1204Crossref PubMed Scopus (732) Google Scholar, 8Wettschureck N. Moers A. Offermanns S. Mouse models to study G-protein-mediated signaling.Pharmacol. Ther. 2004; 101: 75-89Crossref PubMed Scopus (0) Google Scholar, 9Neves S.R. Ram P.T. Iyengar R. G protein pathways.Science. 2002; 296: 1636-1639Crossref PubMed Scopus (898) Google Scholar, 10Wu V. Yeerna H. Nohata N. Chiou J. Harismendy O. Raimondi F. Inoue A. Russell R.B. Tamayo P. Gutkind J.S. 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Despite their central role in GPCR-mediated signal transduction, only a handful of pharmacological agents are available for specific disruption of G protein signaling (14Campbell A.P. Smrcka A.V. Targeting G protein-coupled receptor signalling by blocking G proteins.Nat. Rev. Drug Discov. 2018; 17: 789-803Crossref PubMed Scopus (48) Google Scholar, 15Smrcka A.V. Molecular targeting of Gα and Gβγ subunits: A potential approach for cancer therapeutics.Trends Pharmacol. Sci. 2013; 34: 290-298Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 16Schmitz A.-L. Schrage R. Gaffal E. Charpentier T.H. Wiest J. Hiltensperger G. Morschel J. Hennen S. Häußler D. Horn V. Wenzel D. Grundmann M. Büllesbach K.M. Schröder R. Brewitz H.H. et al.A cell-permeable inhibitor to trap Gαq proteins in the empty pocket conformation.Chem. Biol. 2014; 21: 890-902Abstract Full Text Full Text PDF PubMed Google Scholar, 17Ayoub M.A. Damian M. Gespach C. Ferrandis E. Lavergne O. 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Mechanism of cholera toxin action: Covalent modification of the guanyl nucleotide-binding protein of the adenylate cyclase system.Proc. Natl. Acad. Sci. U. S. A. 1978; 75: 2669-2673Crossref PubMed Google Scholar). Unlike these two bacterial toxins, which act via covalent modification of their cognate Gαi and Gαs subunits, respectively (21Yamane H.K. Fung B.K. Covalent modifications of G-proteins.Annu. Rev. Pharmacol. Toxicol. 1993; 33: 201-241Crossref PubMed Scopus (0) Google Scholar), Gq inhibitors FR900359 (FR) and YM-254890 (YM), two naturally occurring cyclic peptides (22Taniguchi M. Nagai K. Arao N. Kawasaki T. Saito T. Moritani Y. Takasaki J. Hayashi K. Fujita S. Suzuki K. Tsukamoto S. YM-254890, a novel platelet aggregation inhibitor produced by Chromobacterium sp. QS3666.J. Antibiot. 2003; 56: 358-363Crossref PubMed Scopus (62) Google Scholar, 23Fujioka M. Koda S. Morimoto Y. Biemann K. Structure of FR900359, a cyclic depsipeptide from Ardisia crenata sims.J. Org. Chem. 1988; 53: 2820-2825Crossref Scopus (54) Google Scholar), belong to a distinct yet particularly attractive subgroup of noncovalent cell-permeable signaling inhibitors. Mechanistically, both depsipeptides silence function of the Gq family members Gq, G11, and G14 via inhibition of GDP release, the rate-limiting step in G protein activation (24Schrage R. Schmitz A.-L. Gaffal E. Annala S. Kehraus S. Wenzel D. Büllesbach K.M. Bald T. Inoue A. Shinjo Y. Galandrin S. Shridhar N. Hesse M. Grundmann M. Merten N. et al.The experimental power of FR900359 to study Gq-regulated biological processes.Nat. Commun. 2015; 6: 10156Crossref PubMed Google Scholar, 25Nishimura A. Kitano K. Takasaki J. Taniguchi M. Mizuno N. Tago K. Hakoshima T. Itoh H. Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 13666-13671Crossref PubMed Scopus (141) Google Scholar). Thereby, FR and YM lock their cognate Gαβγ heterotrimers in the inactive GDP-bound form. Thus far, both depsipeptides are considered potent and highly selective for Gq over all other Gα families (24Schrage R. Schmitz A.-L. Gaffal E. Annala S. Kehraus S. Wenzel D. Büllesbach K.M. Bald T. Inoue A. Shinjo Y. Galandrin S. Shridhar N. Hesse M. Grundmann M. Merten N. et al.The experimental power of FR900359 to study Gq-regulated biological processes.Nat. Commun. 2015; 6: 10156Crossref PubMed Google Scholar, 25Nishimura A. Kitano K. Takasaki J. Taniguchi M. Mizuno N. Tago K. Hakoshima T. Itoh H. Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 13666-13671Crossref PubMed Scopus (141) Google Scholar, 26Kuschak M. Namasivayam V. Rafehi M. Voss J.H. Garg J. Schlegel J.G. Abdelrahman A. Kehraus S. Reher R. Küppers J. Sylvester K. Hinz S. Matthey M. Wenzel D. 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