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Indomethacin Serves as a Potential Inhibitor of Protein Phosphatases

机译：吲哚美辛作为蛋白磷酸酶的潜在抑制剂

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biBackground/Aims /i/bWe have shown that indomethacin has the potential to activate Ca2+/ calmodulin-dependent protein kinase II (CaMKII), regardless of cyclooxygenase (COX) inhibition. To understand the underlying mechanism, the present study investigated the effect of indomethacin on protein phosphatases such as protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A), and protein tyrosine phosphatase 1B (PTP1B). biMethods /i/bActivity of CaMKII was assayed in cultured rat hippocampal neurons and under the cell-free conditions. Activities of protein phosphatases were monitored under the cell-free conditions. Indomethacin binding assay was carried out using a fluorescein-conjugated indomethacin. biResults /i/bIndomethacin enhanced CaMKII activity in cultured rat hippocampal neurons, that is abolished the CaMKII inhibitor KN-93. In the cell-free assay, no CaMKII activation was obtained with indomethacin, but indomethacin otherwise inhibited PP1 in a concentration (10 µM-1 mM)-dependent manner, the maximum reaching 70% of basal levels. This indicates that indomethacin indirectly activates CaMKII due to PP1 inhibition. Likewise, indomethacin still inhibited PP2A and PTP1B in a concentration (10 µM-1 mM)-dependent manner, reaching 80 and 10% of basal levels at 1 mM, respectively. In the indomethacin binding assay, indomethacin bound to all the investigated protein phosphatases. biConclusion /i/bThe results of the present study indicate that indomethacin inhibits PP1, PP2A, and PTP1B, possibly through its direct binding and that the inhibitory effect of indomethacin on PP1 could cause indirect CaMKII activation. This may represent the novel indomethacin action.
机译：背景/目标 我们已经表明，吲哚美辛具有激活Ca2 + /钙调蛋白依赖性蛋白激酶II（CaMKII）的潜力，而与环氧合酶（COX）的抑制作用无关。为了了解潜在的机制，本研究调查了消炎痛对蛋白质磷酸酶（例如蛋白质磷酸酶1（PP1），蛋白质磷酸酶2A（PP2A）和酪氨酸磷酸酶1B（PTP1B））的作用。 方法 在培养的大鼠海马神经元中和无细胞条件下测定CaMKII的活性。在无细胞条件下监测蛋白磷酸酶的活性。消炎痛结合测定是使用荧光素偶联的消炎痛进行的。 结果 吲哚美辛增强了培养的大鼠海马神经元中CaMKII的活性，从而取消了CaMKII抑制剂KN-93。在无细胞测定中，吲哚美辛未获得CaMKII激活，但吲哚美辛以其他浓度（10 µM-1 mM）依赖性方式抑制PP1，最大浓度达到基础水平的70％。这表明消炎痛由于PP1抑制而间接激活CaMKII。同样，消炎痛仍以浓度（10 µM-1 mM）依赖性方式抑制PP2A和PTP1B，在1 mM时分别达到基础水平的80％和10％。在消炎痛结合试验中，消炎痛与所有研究的蛋白磷酸酶结合。 结论 本研究结果表明吲哚美辛可能通过直接结合抑制PP1，PP2A和PTP1B，并且吲哚美辛对PP1的抑制作用可能导致间接CaMKII激活。这可能代表了新颖的消炎痛作用。

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