Abstract：
The vertebrate retina harbors rod and cone photoreceptors. Human vision critically depends on cone photoreceptor function. In the phototransduction cascade, cGMP activates distinct rod and cone isoforms of the cyclic nucleotide-gated (CNG) channel. Excessive cGMP levels initiate a pathophysiological rollercoaster, which starts with CNG channel over-activation, typically in rod photoreceptors. This triggers cell death of rods first, and then cones, and is the root cause of many blinding retinal diseases, including Retinitis pigmentosa. While targeting of CNG channels has been proposed for therapeutic purposes, thus far, it has not been possible to inhibit rod CNG channels without compromising cone function. Here, we present a novel strategy, based on cGMP analogues with opposing actions on CNG channels, which enables the selective modulation of either rod or cone photoreceptor activity. The combined treatment with the weak rod-selective CNG-channel inhibitor (Rp-8-Br-PET-cGMPS) and the cone-selective CNG-channel activator (8-pCPT-cGMP) essentially normalized rod CNG-channel function while preserving cone functionality at physiological and pathological cGMP levels. Hence, combinations of cGMP analogues with desired properties may elegantly address the isoform-specificity problem in future pharmacological therapies. Moreover, this strategy may allow for improvements in visual performance in certain light environments.
摘要：
脊椎动物视网膜有杆状和锥形光感受器。人类的视觉主要取决于视锥感光体的功能。在光传导级联中，cGMP激活环核苷酸门控(CNG)通道的不同杆状和锥形同种型。过量的cGMP水平引发了病理生理过山车，从CNG通道过度激活开始，通常在杆状光感受器中。这首先触发了棒的细胞死亡，然后是锥体，是许多致盲性视网膜疾病的根本原因，包括色素性视网膜炎.虽然CNG通道的靶向已经被提出用于治疗目的，到目前为止，在不损害锥体功能的情况下抑制棒CNG通道是不可能的。这里,我们提出了一个新的策略，基于在CNG通道上具有相反作用的cGMP类似物，这使得杆或锥感光体活动的选择性调制。弱杆状选择性CNG通道抑制剂（Rp-8-Br-PET-cGMPS）和锥状选择性CNG通道激活剂（8-pCPT-cGMP）的联合治疗基本上使杆状CNG通道功能正常化，同时在生理和病理cGMP水平上保持视锥功能。因此，具有所需性质的cGMP类似物的组合可以在未来的药物治疗中优雅地解决同工型特异性问题。此外，这种策略可以在某些光环境中改善视觉性能。
