Exendin-4 promotes retinal ganglion cell survival and function by inhibiting calcium channels in experimental diabetes

• DOI: 10.1016/j.isci.2023.107680
• Publication Date: 2023-08-18T07:58:24Z
• Authors: Yong-Chen Wang; Lu Wang; Yu-Qi Shao; Shi-Jun Weng; Xiong-Li Yang; Yong-Mei Zhong
• Keywords: Calcium in biology

Progressive damage of retinal ganglion cells (RGCs) is observed in early diabetic retinopathy. Intracellular Ca2+ overload mediated by influx through voltage-gated channels (VGCCs) involved neurodegeneration, whereas glucagon-like peptide-1 (GLP-1) provides neuroprotection. However, whether GLP-1 plays a neuroprotective role retinas modulating VGCCs remains unknown. We found that eye drops exendin-4, long-acting receptor (GLP-1R) agonist, prevented the increase L-type current (ILCa) densities RGCs induced 4-week hyperglycemia and promoted RGC survival suppressing VGCC (L-VGCC) activity streptozotocin-induced rats. Moreover, exendin-4-induced suppression ILCa may be GLP-1R/Gs/cAMP-PKA/ryanodine/Ca2+/calmodulin/calcineurin/PP1 signaling pathway. Furthermore, exendin-4 functionally improved light-evoked spiking ability RGCs. These results suggest GLP-1R activation enhances cAMP to PP1 inactivates L-VGCCs dephosphorylating them, thereby reducing influx, which could protect against excitotoxic overload.