Wang Yong-Chen, Wang Lu, Shao Yu-Qi, Weng Shi-Jun, Yang Xiong-Li, Zhong Yong-Mei
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
iScience. 2023 Aug 18;26(9):107680. doi: 10.1016/j.isci.2023.107680. eCollection 2023 Sep 15.
Progressive damage of retinal ganglion cells (RGCs) is observed in early diabetic retinopathy. Intracellular Ca overload mediated by Ca influx through voltage-gated Ca channels (VGCCs) is involved in neurodegeneration, whereas glucagon-like peptide-1 (GLP-1) provides neuroprotection. However, whether GLP-1 plays a neuroprotective role in diabetic retinas by modulating VGCCs remains unknown. We found that eye drops of exendin-4, a long-acting GLP-1 receptor (GLP-1R) agonist, prevented the increase of L-type Ca current () densities of RGCs induced by 4-week hyperglycemia and promoted RGC survival by suppressing L-type VGCC (L-VGCC) activity in streptozotocin-induced diabetic rats. Moreover, exendin-4-induced suppression of in RGCs may be mediated by a GLP-1R/Gs/cAMP-PKA/ryanodine/Ca/calmodulin/calcineurin/PP1 signaling pathway. Furthermore, exendin-4 functionally improved the light-evoked spiking ability of diabetic RGCs. These results suggest that GLP-1R activation enhances cAMP to PP1 signaling and that PP1 inactivates L-VGCCs by dephosphorylating them, thereby reducing Ca influx, which could protect RGCs against excitotoxic Ca overload.
在早期糖尿病视网膜病变中可观察到视网膜神经节细胞（RGCs）的进行性损伤。通过电压门控钙通道（VGCCs）内流介导的细胞内钙超载参与神经退行性变，而胰高血糖素样肽-1（GLP-1）具有神经保护作用。然而，GLP-1是否通过调节VGCCs在糖尿病视网膜中发挥神经保护作用尚不清楚。我们发现，长效GLP-1受体（GLP-1R）激动剂艾塞那肽-4滴眼液可预防4周高血糖诱导的RGCs L型钙电流（）密度增加，并通过抑制链脲佐菌素诱导的糖尿病大鼠L型VGCC（L-VGCC）活性促进RGCs存活。此外，艾塞那肽-4诱导的RGCs 抑制可能由GLP-1R/Gs/cAMP-PKA/ryanodine/Ca/calmodulin/calcineurin/PP1信号通路介导。此外，艾塞那肽-4在功能上改善了糖尿病RGCs的光诱发尖峰能力。这些结果表明，GLP-1R激活增强了cAMP到PP1的信号传导，并且PP1通过使L-VGCCs去磷酸化使其失活，从而减少钙内流，这可以保护RGCs免受兴奋性毒性钙超载的影响。
