Quan Chao, Xie Bingxian, Wang Hong Yu, Chen Shuai
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210061, China.
PLoS One. 2015 Apr 29;10(4):e0124491. doi: 10.1371/journal.pone.0124491. eCollection 2015.
The Rab GTPase activating protein (RabGAP), AS160/TBC1D4, is an important substrate of protein kinase B (PKB), and regulates insulin-stimulated trafficking of glucose transporter 4. Besides, AS160/TBC1D4 has also been shown to regulate trafficking of many other membrane proteins including FA translocase/CD36 in cardiomyocytes. However, it is not clear whether it plays any role in regulating heart functions in vivo. Here, we found that PKB-mediated phosphorylation of Thr649 on AS160/TBC1D4 represented one of the major PAS-binding signals in the heart in response to insulin. Mutation of Thr649 to a non-phosphorylatable alanine increased the R-wave amplitude in the AS160Thr649Ala knockin mice. However, this knockin mutation did not affect the heart functions under both normal and infarct conditions. Interestingly, myocardial infarction induced the expression of a related RabGAP, TBC1D1, in the infarct zone as well as in the border zone. Together, these data show that the Thr649 phosphorylation of AS160/TBC1D4 plays an important role in the heart's electrical conduction system through regulating the R-wave amplitude.
Rab鸟苷三磷酸酶激活蛋白（RabGAP），即AS160/TBC1D4，是蛋白激酶B（PKB）的重要底物，可调节胰岛素刺激的葡萄糖转运蛋白4的转运。此外，AS160/TBC1D4也已被证明可调节包括心肌细胞中脂肪酸转运体/CD36在内的许多其他膜蛋白的转运。然而，其在体内调节心脏功能方面是否发挥作用尚不清楚。在此，我们发现PKB介导的AS160/TBC1D4上苏氨酸649位点的磷酸化是心脏中响应胰岛素的主要PAS结合信号之一。将苏氨酸649突变为不可磷酸化的丙氨酸会增加AS160Thr649Ala基因敲入小鼠的R波振幅。然而，这种基因敲入突变在正常和梗死条件下均不影响心脏功能。有趣的是，心肌梗死会诱导梗死区以及边缘区中相关RabGAP，即TBC1D1的表达。总之，这些数据表明AS160/TBC1D4的苏氨酸649磷酸化通过调节R波振幅在心脏的电传导系统中发挥重要作用。
