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Characterization of UBO-QIC as a G alpha(q) inhibitor in platelets

机译：UBO-QIC作为血小板中的G alpha（q）抑制剂的表征

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G alpha(q) plays an important role in platelet activation by agonists such as thrombin, adenosine diphosphate (ADP) and thromboxane. The significance of G alpha(q) signaling in platelets was established using YM254890, a G alpha(q/11)-specific inhibitor and G alpha(q) knockout murine platelets. However, YM-254890 is no longer available for investigators and there is a need to characterize other G alpha(q) inhibitors. The aim of this study is to characterize the specificity of a compound, {L-threonine,(3R)-N-acetyl-3-hydroxy-L-leucyl-(aR)-a-hydroxybenzenepropanoyl-2,3-idehydro-N-methylalanyl-L-alanyl-N-methyl-L-alanyl-(3R)-3-[[(2S, 3R)-3-hydroxy-4-methyl-1-oxo-2-[(1-oxo-propyl) amino]pentyl]oxy]-L-leucyl-N,O-dimethyl-,(7 -> 1)-lactone (9CI)} (UBO-QIC), as a G alpha(q) inhibitor in platelets. Human platelets treated with UBO-QIC showed a concentration-dependent inhibition of platelet aggregation and secretion by protease-activated receptors (PAR) agonists, U46619 and ADP. UBO-QIC also abolished G alpha(q) pathway signaling events such as calcium mobilization and pleckstrin phosphorylation. UBO-QIC had no nonspecific effects on the G alpha(12/13) pathway since platelet shape change was intact in G alpha(q) knockout murine platelets stimulated with PAR agonists in the presence of the inhibitor. In addition, UBO-QIC-treated platelets did not affect collagen-related peptide-induced platelet activation suggesting that this inhibitor had no non-specific effects on the GPVI pathway. Furthermore, Akt phosphorylation downstream of the G alpha(i) and G alpha(z) pathways, and vasodilator-stimulated phosphoprotein phosphorylation downstream of the G alpha(s) pathway were not inhibited in UBO-QIC-treated platelets. UBO-QIC is a specific inhibitor for G alpha(q), which can be a useful tool for investigating G alpha(q)-coupled receptor signaling pathways in platelets.
机译：G alpha（q）在凝血酶，二磷酸腺苷（ADP）和血栓烷等激动剂激活血小板的过程中起着重要作用。使用YM254890，G alpha（q / 11）特异性抑制剂和G alpha（q）剔除鼠类血小板，确定了血小板中G alpha（q）信号的重要性。但是，YM-254890不再适用于研究人员，并且需要表征其他G alpha（q）抑制剂。这项研究的目的是表征化合物{L-苏氨酸，（3R）-N-乙酰基-3-羟基-L-亮氨酰-（aR）-α-羟基苯丙酰基-2,3-idehydro-N -甲基丙氨酰基-L-丙氨酰基-N-甲基-L-丙氨酰-（3R）-3-[[（（2S，3R）-3-hydroxy-4-methyl-1-oxo-2-[[1-oxo-propyl ）氨基]戊基]氧基] -L-亮氨酰-N，O-二甲基-，（7→1）-内酯（9CI）}（UBO-QIC），作为血小板中的G alpha（q）抑制剂。用UBO-QIC处理的人血小板通过蛋白酶激活受体（PAR）激动剂U46619和ADP对血小板聚集和分泌表现出浓度依赖性的抑制作用。 UBO-QIC还取消了G alpha（q）途径的信号传导事件，例如钙动员和pleckstrin磷酸化。 UBO-QIC对G alpha（12/13）途径没有非特异性影响，因为在抑制剂存在下，用PAR激动剂刺激的G alpha（q）敲除鼠血小板中血小板的形状完整无缺。此外，UBO-QIC处理的血小板不影响胶原相关肽诱导的血小板活化，表明该抑制剂对GPVI途径没有非特异性作用。此外，在UBO-QIC处理的血小板中，G alpha（i）和G alpha（z）途径下游的Akt磷酸化，以及G alpha（s）途径下游的血管扩张剂刺激的磷蛋白磷酸化均未受到抑制。 UBO-QIC是G alpha（q）的特异性抑制剂，可以作为研究血小板中G alpha（q）偶联的受体信号传导途径的有用工具。

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