PDF(Pubmed)
Abstract：
Photoreceptors in the retina are highly specialized neurons with photosensitive molecules in the outer segment that transform light into chemical and electrical signals, and these signals are ultimately relayed to the visual cortex in the brain to form vision. Photoreceptors are composed of rods and cones. Rods are responsible for dim light vision, whereas cones are responsible for bright light, color vision, and visual acuity. Photoreceptors undergo progressive degeneration over time in many hereditary and age-related retinal diseases. Despite the remarkable heterogeneity of disease-causing genes, environmental factors, and pathogenesis, the progressive death of rod and cone photoreceptors ultimately leads to loss of vision/blindness. There are currently no treatments available for retinal degeneration. Cyclic guanosine 3\', 5\'-monophosphate (cGMP) plays a pivotal role in phototransduction. cGMP governs the cyclic nucleotide-gated (CNG) channels on the plasma membrane of the photoreceptor outer segments, thereby regulating membrane potential and signal transmission. By gating the CNG channels, cGMP regulates cellular Ca2+ homeostasis and signal transduction. As a second messenger, cGMP activates the cGMP-dependent protein kinase G (PKG), which regulates numerous targets/cellular events. The dysregulation of cGMP signaling is observed in varieties of photoreceptor/retinal degenerative diseases. Abnormally elevated cGMP signaling interferes with various cellular events, which ultimately leads to photoreceptor degeneration. In line with this, strategies to reduce cellular cGMP signaling result in photoreceptor protection in mouse models of retinal degeneration. The potential mechanisms underlying cGMP signaling-induced photoreceptor degeneration involve the activation of PKG and impaired Ca2+ homeostasis/Ca2+ overload, resulting from overactivation of the CNG channels, as well as the subsequent activation of the downstream cellular stress/death pathways. Thus, targeting the cellular cGMP/PKG signaling and the Ca2+-regulating pathways represents a significant strategy for photoreceptor protection in retinal degenerative diseases.
摘要：
视网膜中的光感受器是高度特化的神经元，在外段有光敏分子，将光转化为化学和电信号，这些信号最终被传递到大脑的视觉皮层以形成视觉。光感受器由杆和视锥组成。杆负责昏暗的光线视觉，而锥体负责明亮的光线，色觉,和视力。在许多遗传性和年龄相关的视网膜疾病中，光感受器会随着时间的推移而进行性变性。尽管致病基因具有显著的异质性，环境因素,和发病机制，视杆和视锥光感受器的进行性死亡最终导致视力丧失/失明。目前没有可用于视网膜变性的治疗方法。环鸟苷3'，5'-单磷酸盐（cGMP）在光转导中起关键作用。cGMP控制光感受器外段质膜上的环核苷酸门控（CNG）通道，从而调节膜电位和信号传递。通过门控CNG通道，cGMP调节细胞Ca2+稳态和信号转导。作为第二信使，cGMP激活cGMP依赖性蛋白激酶G（PKG），它调节许多目标/细胞事件。在各种光感受器/视网膜变性疾病中观察到cGMP信号传导的失调。异常升高的cGMP信号干扰各种细胞事件，最终导致光感受器退化。与此相符,减少细胞cGMP信号传导的策略导致视网膜变性小鼠模型中的光感受器保护。cGMP信号诱导的光感受器变性的潜在机制涉及PKG的激活和受损的Ca2+稳态/Ca2+过载,由于CNG通道的过度激活，以及下游细胞应激/死亡途径的后续激活。因此，靶向细胞cGMP/PKG信号和Ca2+调节途径代表了视网膜退行性疾病中光感受器保护的重要策略。
