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首页> 外文期刊>Endocrine Research >Novel roles for the rho subfamily of GTP-binding proteins in succinate-induced insulin secretion from betaTC3 cells: further evidence in support of the succinate mechanism of insulin release.
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Novel roles for the rho subfamily of GTP-binding proteins in succinate-induced insulin secretion from betaTC3 cells: further evidence in support of the succinate mechanism of insulin release.

机译：GTP结合蛋白的rho家族的新作用在琥珀酸诱导的βTC3细胞的胰岛素分泌中：支持胰岛素释放琥珀酸机制的进一步证据。

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We have previously demonstrated regulatory roles for Rho subfamily of G-proteins in glucose- and calcium-induced insulin secretion. Herein, we examined regulation by these proteins of insulin secretion from betaTC3 cells elicited by mitochondrial fuels, such as the succinic acid methyl ester (SAME). Preincubation of these cells with Clostridium difficile toxin-B (200 ng/mL), which monoglucosylates and inactivates Cdc42 and Rac1, markedly decreased (> 70%) SAME-induced insulin secretion. Furthermore, exposure of betaTC3 cells to GGTI-2147 (20 microM), a selective inhibitor of the requisite prenylation of Rac1 and Cdc42, significantly reduced (> 80%) SAME-induced insulin release, suggesting that post-translational prenylation of these proteins is necessary for SAME-induced insulin release. Western blot analysis indicated localization of Cdc42, Rac1, and Ras in the beta cell mitochondrial fraction. Confocal microscopy revealed a modest, but inconsistent, increase in the association of either Rac1 or Cdc42with Mitotracker, a mitochondrial marker, following exposure to SAME. These data suggest that activation of preexisting intramitochondrial Rac1 and Cdc42 may be sufficient to regulate SAME-induced insulin secretion. Together, our findings support a role for G-proteins in insulin secretion at a step dependent on mitochondrial metabolism. They also identify mevalonate-derived, isoprenoid modified Rho G-proteins as specific signaling molecules in recently proposed succinate mechanism of insulin release.
机译：我们以前已经证明了G蛋白的Rho亚家族在葡萄糖和钙诱导的胰岛素分泌中的调节作用。在这里，我们检查了这些蛋白质对胰岛素分泌的调节，这些蛋白质是由线粒体燃料（如琥珀酸甲酯（SAME））引起的betaTC3细胞分泌的。将这些细胞与难辨梭状芽孢杆菌毒素B（200 ng / mL）一起预孵育，后者会单糖基化并使Cdc42和Rac1失活，从而显着降低（> 70％）SAME诱导的胰岛素分泌。此外，betaTC3细胞暴露于GGTI-2147（20 microM）（一种必需的Rac1和Cdc42的异戊烯基选择性抑制剂）的暴露，显着降低了（> 80％）SAME诱导的胰岛素释放，表明这些蛋白质的翻译后异戊烯基是SAME诱导的胰岛素释放所必需的。蛋白质印迹分析表明，Cdc42，Rac1和Ras在β细胞线粒体部分中定位。共聚焦显微镜显示，暴露于SAME后，Rac1或Cdc42与线粒体标记物Mitotracker的结合程度适度但不一致。这些数据表明，预先存在的线粒体内Rac1和Cdc42的激活可能足以调节SAME诱导的胰岛素分泌。总之，我们的发现支持G蛋白在依赖线粒体代谢的一步中在胰岛素分泌中的作用。他们还在最近提出的琥珀酸胰岛素释放机制中将甲羟戊酸衍生的，类异戊二烯修饰的Rho G蛋白识别为特定的信号分子。

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