Effects of insulin-like growth factor-1 (IGF-1) receptor signaling on rates of apoptosis in retina of dopamine beta hydroxylase (Dbh-/-) knockout mice.
Effects of insulin-like growth factor-1 (IGF-1) receptor signaling on rates of apoptosis in retina of dopamine beta hydroxylase (Dbh-/-) knockout mice.
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DOI：
10.1016/j.autneu.2009.08.014
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发表时间：
2010-01-15
影响因子：
2.7
通讯作者：
Steinle, Jena J.
中科院分区：
文献类型：
--
作者：
Panjala, Surekha Rani;Thomas, Steven A.;Steinle, Jena J.
我们研究了胰岛素样生长因子-1（IGF-1）受体信号传导是否改变多巴胺β-羟化酶（Dbh-/-）敲除小鼠的凋亡率。来自Dbh-/-及其杂合子同窝出生仔（Dbh+/-）的视网膜裂解物用于检查去甲肾上腺素在视网膜中的IGF-1受体信号传导和细胞凋亡的调节中的作用。对总的和磷酸化的IGF-1受体、胰岛素受体底物-1（IRS-1）、胰岛素受体底物-2（IRS-2）和Akt的蛋白水平进行蛋白质印迹分析。对视网膜裂解物进行胱天蛋白酶3 ELISA和多巴胺ELISA。为了验证视网膜的哪些区域正在经历细胞凋亡，进行TUNEL标记。在KO和杂合子小鼠之间没有观察到多巴胺的变化。与其杂合子同窝小鼠相比，Dbh-/-小鼠中IGF-1受体磷酸化显著降低（与杂合子小鼠相比，P<0.05）。IRS-1蛋白磷酸化在KO小鼠中显著降低（与杂合子小鼠相比P<0.05），而IRS-2蛋白磷酸化没有显著变化。Akt蛋白磷酸化在KO小鼠中也减少，可能导致裂解的半胱天冬酶3水平增加。Dbh-/-小鼠中细胞凋亡的增加主要发生在视网膜内层。我们的研究结果表明，IGF-1受体信号减少，在视网膜功能障碍的肾上腺素能受体信号。这些数据还表明，IGF-1受体信号主要通过IRS-1而不是IRS-2发生。Akt磷酸化的减少，可能通过减少IGF-1受体信号传导，可以解释裂解的caspase 3的增加，导致细胞凋亡。这些结果表明，肾上腺素能受体信号的改变调节IGF-1受体信号，这可以调节视网膜中的细胞凋亡。
We have investigated whether insulin-like growth factor-1 (IGF-1) receptor signaling alters rates of apoptosis in dopamine beta-hydroxylase (Dbh-/-) knockout mice. Retinal lysates from Dbh-/- and their heterozygote littermates (Dbh+/-) were used to examine the role of norepinephrine in the regulation of IGF-1 receptor signaling and apoptosis in the retina. Western blot analysis was done for protein levels of total and phosphorylated IGF-1 receptor, insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), and Akt. A caspase 3 ELISA and dopamine ELISA were done on retinal lysates. To verify which regions of the retina were undergoing apoptosis, TUNEL labeling was performed. No changes in dopamine were noted between the KO and heterozygote mice. IGF-1 receptor phosphorylation was significantly decreased in Dbh-/- mice as compared to their heterozygote littermates (P<0.05 vs. heterozygous mice). IRS-1 protein phosphorylation was significantly decreased in KO mice (P<0.05 vs. heterozygous mice), while no significant changes were noted in IRS-2 protein phosphorylation. Akt protein phosphorylation was also reduced in the KO mice, likely leading to increased cleaved caspase 3 levels. The increase in apoptosis in the Dbh-/- mice occurred predominantly in the inner retina. Our results suggest that IGF-1 receptor signaling is reduced in the retina of mice with dysfunctional adrenergic receptor signaling. The data also indicate that IGF-1 receptor signaling occurs primarily through IRS-1, rather than IRS-2. The reduction in Akt phosphorylation, likely through reduced IGF-1 receptor signaling, could explain the increase in cleaved caspase 3, leading to apoptosis. These results suggest that alterations in adrenergic receptor signaling modulate IGF-1 receptor signaling, which can regulate apoptosis in the retina.
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