Activation of the JAK-STAT pathway by olanzapine is necessary for desensitization of serotonin2A receptor-stimulated phospholipase C signaling in rat frontal cortex but not serotonin2A receptor-stimulated hormone release.
Activation of the JAK-STAT pathway by olanzapine is necessary for desensitization of serotonin2A receptor-stimulated phospholipase C signaling in rat frontal cortex but not serotonin2A receptor-stimulated hormone release.
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DOI：
10.1177/0269881109103090
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发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Muma NA
中科院分区：
文献类型：
--
作者：
Singh RK;Jia C;Garcia F;Carrasco GA;Battaglia G;Muma NA
奥氮平长期治疗可导致奥氮平2A受体信号转导脱敏。本研究的目的是进一步了解这种脱敏反应背后的机制，在体内的阿托伐他汀2A受体信号转导。我们现在报告说，奥氮平诱导的大鼠额叶皮层中的降钙素2A受体刺激的磷脂酶C活性的脱敏依赖于JAK-STAT通路的激活。奥氮平治疗7天可显著增加大鼠额叶皮质中G蛋白信号调节因子（RGS 7）蛋白水平、RGS 7 mRNA水平和JAK 2活化。JAK 2抑制剂AG 490预处理显著减弱了奥氮平诱导的降钙素2A受体刺激的磷脂酶C活性降低，并阻止了奥氮平诱导的RGS 7 mRNA和蛋白水平升高。相比之下，用AG 490抑制JAK-STAT通路并不能逆转奥氮平诱导的下丘脑室旁核中介导血浆激素水平升高的降钙素2A受体通路的脱敏。AG 490剂量依赖性地抑制催产素2A受体刺激的催产素和皮质酮的释放。综上所述，这些结果表明，奥氮平诱导的RGS 7表达的增加是由JAK-STAT的激活介导的，并且是奥氮平诱导的额叶皮质中的降钙素2A受体刺激的磷脂酶C活性的脱敏所必需的，但不是降钙素2A受体刺激的激素释放。
Chronic treatment with olanzapine causes desensitization of serotonin2A receptor signaling. The purpose of the current study is to further understand the mechanisms underlying this desensitization response of serotonin2A receptor signaling in vivo. We now report that desensitization of serotonin2A receptor stimulated-phospholipase C activity in rat frontal cortex induced by olanzapine is dependent on activation of the JAK-STAT pathway. Olanzapine treatment for 7 days significantly increased the levels of the regulator of G protein signaling (RGS7) protein, RGS7 mRNA levels, and activation of JAK2 in rat frontal cortex. Pretreatment with a JAK2 inhibitor AG490, significantly attenuated the olanzapine-induced reductions in serotonin2A receptor-stimulated phospholipase C activity and prevented the olanzapine-induced increases in RGS7 mRNA and protein levels. In contrast, inhibition of the JAK-STAT pathway with AG490 did not reverse the olanzapine-induced desensitization of the serotonin2A receptor pathway in the hypothalamic paraventricular nucleus mediating increases in plasma hormone levels. AG490 dose-dependently inhibited serotonin2A receptor-stimulated oxytocin and corticosterone release. Taken together, these results suggest that the olanzapine-induced increase in RGS7 expression is mediated by activation of JAK-STAT and is necessary for olanzapine-induced desensitization of serotonin2A receptor-stimulated phospholipase C activity in the frontal cortex but not serotonin2A receptor-stimulated hormone release.
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