Zhao Guo-Li, Zhou Hong, Guo Yun-Hui, Zhong Shu-Min, Zhou Han, Li Fang, Lei Bo, Wang Zhongfeng, Miao Yanying
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
Institute of Neuroscience and Third Affiliated Hospital, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
Glia. 2023 Jun;71(6):1502-1521. doi: 10.1002/glia.24354. Epub 2023 Feb 16.
Connexin43 (Cx43) is a major gap junction protein in glial cells. Mutations have been found in the gap-junction alpha 1 gene encoding Cx43 in glaucomatous human retinas, suggestive of the involvement of Cx43 in the pathogenesis of glaucoma. However, how Cx43 is involved in glaucoma is still unknown. We showed that increased intraocular pressure in a glaucoma mouse model of chronic ocular hypertension (COH) downregulated Cx43, which was mainly expressed in retinal astrocytes. Astrocytes in the optic nerve head where they gather and wrap the axons (optic nerve) of retinal ganglion cells (RGCs) were activated earlier than neurons in COH retinas and the alterations in astrocytes plasticity in the optic nerve caused a reduction in Cx43 expression. A time course showed that reductions of Cx43 expression were correlated with the activation of Rac1, a member of the Rho family. Co-immunoprecipitation assays showed that active Rac1, or the downstream signaling effector PAK1, negatively regulated Cx43 expression, Cx43 hemichannel opening and astrocyte activation. Pharmacological inhibition of Rac1 stimulated Cx43 hemichannel opening and ATP release, and astrocytes were identified to be one of the main sources of ATP. Furthermore, conditional knockout of Rac1 in astrocytes enhanced Cx43 expression and ATP release, and promoted RGC survival by upregulating the adenosine A3 receptor in RGCs. Our study provides new insight into the relationship between Cx43 and glaucoma, and suggests that regulating the interaction between astrocytes and RGCs via the Rac1/PAK1/Cx43/ATP pathway may be used as part of a therapeutic strategy for managing glaucoma.
连接蛋白43（Cx43）是神经胶质细胞中的一种主要缝隙连接蛋白。在青光眼患者视网膜中，已发现编码Cx43的缝隙连接α1基因发生突变，这表明Cx43参与了青光眼的发病机制。然而，Cx43如何参与青光眼的发病仍不清楚。我们发现，慢性高眼压（COH）青光眼小鼠模型中眼压升高会下调Cx43，Cx43主要在视网膜星形胶质细胞中表达。在视神经乳头处，聚集并包裹视网膜神经节细胞（RGCs）轴突（视神经）的星形胶质细胞比COH视网膜中的神经元更早被激活，并且视神经中星形胶质细胞可塑性的改变导致Cx43表达降低。时间进程显示，Cx43表达的降低与Rho家族成员Rac1的激活相关。免疫共沉淀分析表明，活性Rac1或下游信号效应器PAK1负向调节Cx43表达、Cx43半通道开放和星形胶质细胞激活。Rac1的药理学抑制刺激了Cx43半通道开放和ATP释放，并且星形胶质细胞被确定为ATP的主要来源之一。此外，星形胶质细胞中Rac1的条件性敲除增强了Cx43表达和ATP释放，并通过上调RGCs中的腺苷A3受体促进了RGCs存活。我们的研究为Cx43与青光眼之间的关系提供了新的见解，并表明通过Rac1/PAK1/Cx43/ATP途径调节星形胶质细胞与RGCs之间的相互作用可能用作治疗青光眼的治疗策略的一部分。
