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

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.