Gao Zhan-Guo, Jacobson Kenneth A
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Biochem Pharmacol. 2016 May 1;107:59-66. doi: 10.1016/j.bcp.2016.03.003. Epub 2016 Mar 5.
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.
Gαq抑制剂UBO-QIC（FR900359）正成为一种重要的药理学工具，但其对其他G蛋白及其亚基，尤其是βγ的选择性尚未得到充分表征。我们通过与已知的Gαi抑制剂百日咳毒素比较，研究了UBO-QIC对经由各种G蛋白偶联受体（GPCR）和G蛋白亚基介导的多种信号通路的影响。正如预期的那样，UBO-QIC在所有检测系统中均抑制了Gαq信号传导。然而，在Gi偶联的A1腺苷受体和M2毒蕈碱型乙酰胆碱受体激活后，其他非Gαq事件，如Gβγ介导的细胞内钙释放和肌醇磷酸生成，也被低浓度的UBO-QIC阻断，这表明其作用不限于Gαq。因此，尽管UBO-QIC不影响Gαi介导的抑制或Gαs介导的腺苷酸环化酶活性刺激，但它也与百日咳毒素类似地抑制Gβγ介导的信号传导。然而，UBO-QIC对GPCR信号传导的阻断，如卡巴胆碱或腺苷介导的钙或肌醇磷酸增加，并不总是表明对Gαq介导事件的抑制，因为在Gi偶联受体（如M2和A1R）激活后从Gi蛋白释放的βγ亚基可能产生类似的信号事件。此外，UBO-QIC完全抑制了Akt信号传导，但仅部分阻断了由Gq偶联的P2Y1R刺激的ERK1/2活性。因此，我们揭示了UBO-QIC药理学相互作用的新方面。
