On the selectivity of the Gαq inhibitor UBO-QIC: A comparison with the Gαi inhibitor pertussis toxin

• Published in: Biochemical pharmacology 2016-05, Vol.107, p.59-66
• Main Authors: Gao, Zhan-Guo, Jacobson, Kenneth A.
• Format: Article
• Language: English
• Subjects: Animals; CHO Cells; Cricetulus; Depsipeptides - pharmacology; Enzyme Inhibitors - pharmacology; FR900359; G protein; GPCR; GTP-Binding Protein alpha Subunits, Gi-Go - agonists; GTP-Binding Protein alpha Subunits, Gi-Go - antagonists & inhibitors; GTP-Binding Protein alpha Subunits, Gi-Go - genetics; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; GTP-Binding Protein alpha Subunits, Gq-G11 - antagonists & inhibitors; GTP-Binding Protein alpha Subunits, Gq-G11 - chemistry; GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism; GTP-Binding Protein beta Subunits - agonists; GTP-Binding Protein beta Subunits - antagonists & inhibitors; GTP-Binding Protein beta Subunits - metabolism; GTP-Binding Protein gamma Subunits - agonists; GTP-Binding Protein gamma Subunits - antagonists & inhibitors; GTP-Binding Protein gamma Subunits - metabolism; Gαq inhibitor; Gβγ subunits; HEK293 Cells; Humans; MAP Kinase Signaling System - drug effects; Models, Biological; Pertussis Toxin - pharmacology; Platelet Aggregation Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - agonists; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Adenosine A1 - chemistry; Receptor, Adenosine A1 - genetics; Receptor, Adenosine A1 - metabolism; Receptor, Muscarinic M2 - agonists; Receptor, Muscarinic M2 - antagonists & inhibitors; Receptor, Muscarinic M2 - genetics; Receptor, Muscarinic M2 - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Signal Transduction - drug effects; UBO-QIC
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2016.03.003

[Display omitted] 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.