Glutamate accelerates RPE cell proliferation through ERK1/2 activation via distinct receptor-specific mechanisms
Glutamate accelerates RPE cell proliferation through ERK1/2 activation via distinct receptor-specific mechanisms
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DOI：
10.1002/jcb.21633
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发表时间：
2008-05-15
影响因子：
4
通讯作者：
Lopez-Colome, Ana Maria
中科院分区：
文献类型：
--
作者：
Garcia, Sofia;Lopez, Edith;Lopez-Colome, Ana Maria
上皮-间质转化引起的视网膜色素上皮细胞的增殖和迁移在增殖性玻璃体视网膜病变中起关键作用，从而导致视网膜脱离和视力丧失。在神经元中，谷氨酸已被证明可以激活 Ras/Raf/MEK/ERK 级联，参与增殖、分化和存活过程的调节。尽管谷氨酸刺激和不同刺激对 ERK1/2 的激活已被证明可以促进 RPE 细胞增殖，但连接这些效应的信号传导途径尚未建立。我们通过测定原代培养的鸡 RPE 细胞和人源 RPE 细胞系 ARPE-19 中的 ERK1/2 和 CREB 磷酸化，分析了导致谷氨酸增殖的分子机制。这项研究首次表明，谷氨酸通过激活与选择性谷氨酸受体亚型相关的两种不同的信号通路来促进 RPE 细胞增殖。结果表明，谷氨酸刺激 RPE 细胞增殖以及 ERK 和 CREB 磷酸化。这些作用被mG11uR激动剂ACPD和NMDA模拟，并被各自的受体抑制剂MCPG和MK-801阻止，表明这些过程之间存在因果关系。 mGluR 通过激活 MEK/ERK/CREB 级联来促进增殖，而 NMDA 通过不依赖于 MEK 的 Ca2+/钙调蛋白依赖性激酶的激活来刺激增殖。 KN-62 对两条增殖信号通路的阻断表明 CaMK 参与控制谷氨酸诱导的增殖，在 CREB 下游的一个共同步骤中，可能是细胞周期进程的调节。基于这些发现，可以考虑谷氨酸参与 PVR 的发展。
The proliferation and migration of Retinal Pigment Epithelium cells resulting from an epithelial-mesenchymal transition plays a key role in proliferative vitreoretinopathy, which leads to retinal detachment and the loss of vision. In neurons, glutamate has been shown to activate the Ras/Raf/MEK/ERK cascade, which participates in the regulation of proliferation, differentiation, and survival processes. Although glutamate-stimulation and the activation of ERK1/2 by different stimuli have been shown to promote RPE cell proliferation, the signaling pathway(s) linking these effects has not been established. We analyzed the molecular mechanisms leading to glutamate-incluced proliferation by determining ERK1/2 and CREB phoshporylation in chick RPE cells in primary culture and the human-derived RPE cell line ARPE-19. This study shows for the first time, that glutamate promotes RPE cell proliferation by activating two distinct signaling pathways linked to selective glutamate receptor subtypes. Results demonstrate that glutamate stimulates RPE cell proliferation as well as ERK and CREB phosphorylation. These effects were mimicked by the mGl\uR agonist ACPD and by NMDA, and were prevented by the respective receptor inhibitors MCPG and MK-801, indicating a cause-effect relationship between these processes. Whereas mGluR promoted proliferation by activating the MEK/ERK/CREB cascade, NMDA stimulated proliferation through the MEK-independent activation of Ca2+/calmodulin-dependent kinases. The blockage of both signaling pathways to proliferation by KN-62 suggests the involvement of CaMKs in the control of glutamate-induced proliferation at a common step, downstream of CREB, possibly the regulation of cell cycle progression. Based on these findings, the participation of glutamate in the development of PVR can be considered.