Activation of the JAK-STAT pathway is necessary for desensitization of 5-HT2A receptor-stimulated phospholipase C signalling by olanzapine, clozapine and MDL 100907.
Activation of the JAK-STAT pathway is necessary for desensitization of 5-HT2A receptor-stimulated phospholipase C signalling by olanzapine, clozapine and MDL 100907.
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JAK-STAT 通路的激活对于奥氮平、氯氮平和 MDL 100907 使 5-HT2A 受体刺激的磷脂酶 C 信号转导脱敏是必要的。
DOI：
10.1017/s1461145708009590
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Muma,NancyA
中科院分区：
文献类型：
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作者：
Singh,RakeshK;Dai,Ying;Staudinger,JeffL;Muma,NancyA
我们先前已经证明，奥氮平诱导的5-HT 2A受体刺激的磷脂酶C（PLC）活性的脱敏与体内和培养细胞中RGS 7蛋白水平的增加有关，并且RGS 7的增加依赖于培养细胞中JAK-STAT通路的激活。在本研究中，我们发现奥氮平诱导的5-HT 2A受体刺激的PLC活性的脱敏依赖于JAK-STAT通路的激活。与奥氮平相似，氯氮平诱导的5-HT 2A受体信号转导脱敏伴随着RGS 7的增加和JAK 2的激活。用选择性5-HT 2A受体拮抗剂MDL 100907处理也增加RGS 7蛋白水平和JAK 2活化。使用JAK 2抑制剂AG 490，我们发现氯氮平和MDL 100907诱导的RGS 7增加依赖于JAK-STAT通路的激活。奥氮平、氯氮平和MDL 100907处理增加RGS 7的mRNA水平。使用染色质免疫沉淀分析，我们发现STAT 3结合到假定的RGS 7启动子区域。总之，奥氮平诱导的JAK-STAT途径活化和STAT 3与RGS 7基因的结合可能是RGS 7 mRNA增加的基础，随后可增加蛋白表达。此外，RGS 7蛋白的增加可能通过更快地终止激活的Gαq/11蛋白而在5-HT 2A受体信号转导的脱敏中起作用。总体而言，我们的数据表明，奥氮平，氯氮平和MDL 100907对5-HT 2A受体刺激的PLC活性的完全脱敏需要激活JAK-STAT途径，这反过来可能通过STAT 3的直接转录活性增加RGS 7表达。
We have previously demonstrated that olanzapine-induced desensitization of 5-HT2Areceptor-stimulated phospholipase C (PLC) activity is associated with increases in RGS7 protein levels both in vivo and in cells in culture, and the increase in RGS7 is dependent on activation of the JAK-STAT pathway in cells in culture. In the present study, we found that desensitization of 5-HT2Areceptor-stimulated PLC activity induced by olanzapine is dependent on activation of the JAK-STAT pathway. Similar to olanzapine, clozapine-induced desensitization of 5-HT2Areceptor signalling is accompanied by increases in RGS7 and activation of JAK2. Treatment with the selective 5-HT2Areceptor antagonist MDL 100907 also increased RGS7 protein levels and JAK2 activation. Using a JAK2 inhibitor AG490, we found that clozapine and MDL 100907-induced increases in RGS7 are dependent on activation of the JAK-STAT pathway. Olanzapine, clozapine, and MDL 100907 treatment increased mRNA levels of RGS7. Using a chromatin immunoprecipitation assay we found STAT3 binding to the putative RGS7 promoter region. Taken together, olanzapine-induced activation of the JAK-STAT pathway, and STAT3 binding to the RGS7 gene could underlie the increase in RGS7 mRNA which could subsequently increase protein expression. Furthermore, the increase in RGS7 protein could play a role in the desensitization of 5-HT2Areceptor signalling by terminating the activated Gαq/11proteins more rapidly. Overall, our data suggest that the complete desensitization of 5-HT2Areceptor-stimulated PLC activity by olanzapine, clozapine and MDL 100907 requires activation of the JAK-STAT pathway, which in turn increases RGS7 expression probably by direct transcriptional activity of STAT3.