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

Yong-Chen Wang; Lu Wang; Yu-Qi Shao; Shi-Jun Weng; Xiong-Li Yang; Yong-Mei Zhong

doi:10.1016/j.isci.2023.107680

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

iScience. 2023 Aug 18;26(9):107680. doi: 10.1016/j.isci.2023.107680. eCollection 2023 Sep 15.

Authors

Yong-Chen Wang¹, Lu Wang¹, Yu-Qi Shao¹, Shi-Jun Weng¹, Xiong-Li Yang¹, Yong-Mei Zhong¹

Affiliation

¹ 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.

Abstract

Progressive damage of retinal ganglion cells (RGCs) is observed in early diabetic retinopathy. Intracellular Ca²⁺ overload mediated by Ca²⁺ influx through voltage-gated Ca²⁺ 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 Ca²⁺ current (I_LCa) 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 I_LCa in RGCs may be mediated by a GLP-1R/Gs/cAMP-PKA/ryanodine/Ca²⁺/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 Ca²⁺ influx, which could protect RGCs against excitotoxic Ca²⁺ overload.

Keywords: Endocrine regulation; Endocrinology; Molecular biology.