title: On the selectivity of the Gαq inhibitor UBO-QIC: A comparison with the Gαi inhibitor pertussis toxin.
abstract: Gαq inhibitor UBO-QIC (FR900359) is becoming an important pharmacological tool, but its selectivity against other G proteins and their subunits, especially βγ, has not been well characterized. We examined UBO-QIC's effect on diverse signaling pathways mediated via various G protein-coupled receptors (GPCRs) and G protein subunits by comparison with known Gαi inhibitor pertussis toxin. As expected, UBO-QIC inhibited Gαq signaling in all assay systems examined. However, other non-Gαq-events, e.g. Gβγ-mediated intracellular calcium release and inositol phosphate production, following activation of Gi-coupled A1 adenosine and M2 muscarinic acetylcholine receptors, were also blocked by low concentrations of UBO-QIC, indicating that its effect is not limited to Gαq. Thus, UBO-QIC also inhibits Gβγ-mediated signaling similarly to pertussis toxin, although UBO-QIC does not affect Gαi-mediated inhibition or Gαs-mediated stimulation of adenylyl cyclase activity. However, the blockade by UBO-QIC of GPCR signaling, such as carbachol- or adenosine-mediated calcium or inositol phosphate increases, does not always indicate inhibition of Gαq-mediated events, as the βγ subunits released from Gi proteins following the activation of Gi-coupled receptors, e.g. M2 and A1Rs, may produce similar signaling events. Furthermore, UBO-QIC completely inhibited Akt signaling, but only partially blocked ERK1/2 activity stimulated by the Gq-coupled P2Y1R. Thus, we have revealed new aspects of the pharmacological interactions of UBO-QIC.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. Electronic address: zg21o@nih.gov.
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. Electronic address: kennethj@helix.nih.gov.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D047630:Depsipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D037342:Pertussis Toxin / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C487078:CHRM2 protein, human; D047630:Depsipeptides; D004791:Enzyme Inhibitors; C000607068:FR900359; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D010975:Platelet Aggregation Inhibitors; D043682:Receptor, Adenosine A1; D043585:Receptor, Muscarinic M2; D011994:Recombinant Proteins; D037342:Pertussis Toxin; D051057:Proto-Oncogene Proteins c-akt; C584114:GNAI1 protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: FR900359; G protein; GPCR; Gα(q) inhibitor; Gβγ subunits; UBO-QIC