The anti-diabetic bis(maltolato)oxovanadium(IV) decreases lipid order while increasing insulin receptor localization in membrane microdomains.
The anti-diabetic bis(maltolato)oxovanadium(IV) decreases lipid order while increasing insulin receptor localization in membrane microdomains.
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抗糖尿病双（麦芽糖）氧钒 (IV) 会降低脂质顺序，同时增加膜微区中胰岛素受体的定位。
DOI：
10.1039/c2dt30521f
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Crans,DebbieC
中科院分区：
文献类型：
--
作者：
Winter,PeterW;Al-Qatati,Abeer;Wolf-Ringwall,AmberL;Schoeberl,Samantha;Chatterjee,PabitraB;Barisas,BGeorge;Roess,DeborahA;Crans,DebbieC
通过比较胰岛素和BMOV处理对单个胰岛素受体（IR）的侧向运动和区室化的影响，研究了BMOV处理对膜微区蛋白定位的影响。此外，胰岛素和BMOV对IR、磷酸化IR（pIR）和磷酸化胰岛素受体底物-1（pIRS-1）与大鼠嗜碱性白血病（RBL-2 H3）细胞上化学分离的质膜微区的缔合的影响进行了评价。单粒子追踪实验表明，RBL-2 H3细胞上的单个量子点标记的IR表现出相对不受限制的侧向扩散，约为1 × 10−10 cm 2 s−1，并被限制在直径约为475 nm的细胞表面膜室中。用10 μM BMOV处理RBL-2 H3细胞后，IR侧向扩散和含IR膜隔室的尺寸分别显着减少至6 × 10 - 11 cm 2 s-1和约400 nm。BMOV处理还增加了IR与使用等密度蔗糖梯度离心分离的低密度、耐洗涤剂的膜碎片的关联，从未处理细胞的2.4%增加到用10 μM BMOV处理的细胞的25.8%。此外，用基于相敏氨基萘基乙烯基吡啶鎓的染料Di-4-ANEPPDHQ标记的活RBL-2 H3细胞的共聚焦荧光显微镜成像表明，BMOV处理而不是胰岛素处理降低了细胞表面质膜脂质顺序，而荧光相关光谱测量表明，BMOV处理不影响IR表面密度或胰岛素结合亲和力。最后，使用十六烷基三甲基溴化铵（CTAB）胶束和1H NMR光谱的微乳液模型研究表明，氧化形式的BMOV容易本地化附近的CTAB头基在脂-水界面。这些观察结果得到了支持的红外光谱研究，使用微乳液的CTAB反胶束显示，BMOV和氧化的BMOV与水池。这一结论是基于观察到的复杂的氧化BMOV的1H NMR化学位移的变化。此外，这些变化似乎提供了有关该建筑群位置的信息。在存在和不存在BMOV、氧化BMOV或麦芽酚的情况下制备的CTAB反胶束的OD吸收峰位置没有观察到差异。结合起来，这些结果表明，胰岛素和BMOV治疗的IR信号的激活涉及IR与专门的纳米级膜微区的增加的关联。观察到的胰岛素样活性的BMOV或BMOV的分解产物可能是由于细胞表面膜脂质顺序的变化，而不是由于与IR的直接相互作用。
The effects of treatment with bis(maltolato)oxovanadium(IV) (BMOV) on protein localization in membrane microdomains were investigated by comparing the effects of insulin and treatment with BMOV on the lateral motions and compartmentalization of individual insulin receptors (IR). In addition, effects of insulin and BMOV on the association of IR, phosphorylated IR (pIR) and phosphorylated insulin receptor substrate-1 (pIRS-1) with chemically-isolated plasma membrane microdomains on rat basophilic leukemia (RBL-2H3) cells were evaluated. Single particle tracking experiments indicate that individual quantum dot-labeled IR on RBL-2H3 cells exhibit relatively unrestricted lateral diffusion of approximately 1 × 10−10 cm2 s−1 and are confined in approximately 475 nm diameter cell-surface membrane compartments. After treating of RBL-2H3 cells with 10 μM BMOV, IR lateral diffusion and the size of IR-containing membrane compartments is significantly reduced to 6 × 10−11 cm2 s−1 and approximately 400 nm, respectively. BMOV treatment also increases the association of IR with low-density, detergent-resistant membrane fragments isolated using isopycnic sucrose-gradient centrifugation from 2.4% for untreated cells to 25.8% for cells treated with 10 μM BMOV. Additionally, confocal fluorescence microscopic imaging of live RBL-2H3 cells labeled with the phase sensitive aminonaphthylethenylpyridinium-based dye, Di-4-ANEPPDHQ, indicates that BMOV treatment, but not insulin treatment, decreases cell-surface plasma membrane lipid order while fluorescence correlation spectroscopy measurements suggest that BMOV treatment does not affect IR surface-density or insulin binding affinity. Finally, model studies using microemulsions of cetyltrimethylammonium bromide (CTAB) micelles and 1H NMR spectroscopy show that an oxidized form of BMOV readily localizes near the CTAB head-groups at the lipid–water interface. These observations were supported by IR spectroscopic studies using microemulsions of CTAB reverse micelles showing that both BMOV and oxidized BMOV are associated with the water pool. This conclusion is based on changes in 1H NMR chemical shifts observed for the complex, oxidized BMOV. Moreover, these shifts appeared to be informative about the location of the complex. No differences were observed in the OD absorption peak positions for the CTAB reverse micelles prepared in the presence and absence of BMOV, oxidized BMOV or maltol. Combined, these results suggest that activation of IR signaling by both insulin and BMOV treatment involves increased association of IR with specialized, nanoscale membrane microdomains. The observed insulin-like activity of BMOV or decomposition products of BMOV may be due to changes in cell-surface membrane lipid order rather than due to direct interactions with IR.
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