M2毒蕈碱受体拮抗剂通过激活豚鼠视网膜中的Kir3.4通道延缓近视发展的证据。

Evidence for M2 Muscarinic Receptor Antagonist Delay of Myopia Development Through Activation of Kir3.4 Channel in the Retina of Guinea Pigs.

作者信息

Zhou Hong, Zhou Guimei, Yang Qin, Niu Jiahao, Wang Runzhe, Liu Huilan, Hou Suwen, Bi Hongsheng, Liao Xuan

机构信息

Department of Ophthalmology of Affiliated Hospital, Medical School of Ophthalmology and Optometry, North Sichuan Medical College, Nanchong, Sichuan Province, China.

Affiliated Eye Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.

出版信息

Invest Ophthalmol Vis Sci. 2025 Jul 1;66(9):5. doi: 10.1167/iovs.66.9.5.

DOI:10.1167/iovs.66.9.5

PMID:40600764

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12227029/

Abstract

PURPOSE

The purpose of this study was to investigate the association between muscarinic receptor M2 and potassium channel Kir3.4 encoded by gene KCNJ5, as well as their role in guinea pigs with form deprivation myopia (FDM).

METHODS

One hundred sixty-five 3-week-old guinea pigs were randomly assigned to the following groups: normal control (NC), self-control (SC), form deprivation (FD), lentiviral vector (FD + Vector), KCNJ5 overexpression lentivirus (FD + KCNJ5-OE), vehicle control (FD + DMSO), M2 receptor antagonist (FD + AF-DX 116), and M2 receptor agonist (FD + LY2119620). The association between M2 receptors and retinal potassium channels and effects of retinal K+ concentration on myopia development were investigated by constructing a lentiviral KCNJ5 overexpression and M2 receptor intervention model. Immunohistochemistry and molecular assays were conducted to measure the distribution and expression of Kir3.4-related mRNA and protein in the retina. TUNEL was used to observe the drug toxicity response on the retina.

RESULTS

The FD group had higher myopic degree (all P < 0.001) and lower expression levels of Kir3.4 than the NC group (P = 0.008). The FD + KCNJ5-OE group exhibited upregulated Kir3.4 protein expression (P < 0.001), but a significant decrease in myopia degree and K+ concentration (all P < 0.001) compared with the FD + Vector group. The FD + AF-DX 116 group exhibited lower myopic degree, K+ concentration (all P < 0.05), and higher Kir3.4 protein expression (P < 0.001), as well as the FD + LY2119620 group exhibited significantly upregulated myopia degree and K+ concentration (all P < 0.001) compared with the FD + DMSO group.

CONCLUSIONS

This study is the first to explore the muscarinic receptor-potassium channel connection and its implications in the development of myopia. The M2 receptor may be involved in the development of myopia by regulating retinal Kir3.4 channel and K+ homeostasis.

摘要

目的

本研究旨在探讨毒蕈碱受体M2与由基因KCNJ5编码的钾通道Kir3.4之间的关联，以及它们在豚鼠形觉剥夺性近视（FDM）中的作用。

方法

将165只3周龄豚鼠随机分为以下几组：正常对照组（NC）、自身对照组（SC）、形觉剥夺组（FD）、慢病毒载体组（FD + Vector）、KCNJ5过表达慢病毒组（FD + KCNJ5 - OE）、溶剂对照组（FD + DMSO）、M2受体拮抗剂组（FD + AF - DX 116）和M2受体激动剂组（FD + LY2119620）。通过构建慢病毒KCNJ5过表达和M2受体干预模型，研究M2受体与视网膜钾通道之间的关联以及视网膜K⁺浓度对近视发展的影响。进行免疫组织化学和分子检测以测量视网膜中Kir3.4相关mRNA和蛋白的分布及表达。采用TUNEL法观察药物对视网膜的毒性反应。

结果

与NC组相比，FD组近视度数更高（所有P < 0.001），Kir3.4表达水平更低（P = 0.008）。与FD + Vector组相比，FD + KCNJ5 - OE组Kir3.4蛋白表达上调（P < 0.001），但近视度数和K⁺浓度显著降低（所有P < 0.001）。与FD + DMSO组相比，FD + AF - DX 116组近视度数、K⁺浓度更低（所有P < 0.05），Kir3.4蛋白表达更高（P < 0.001），FD + LY2119620组近视度数和K⁺浓度显著上调（所有P < 0.001）。