College of Osteopathic Medicine, Touro University, Henderson, NV 89014, USA.
Mol Cell Biochem. 2010 Jan;334(1-2):125-39. doi: 10.1007/s11010-009-0323-y. Epub 2009 Nov 26.
Membranous guanylate cyclase in retinal photoreceptor outer segments (ROS-GC), a key enzyme for the recovery of photoreceptors to the dark state, has a topology identical to and cytoplasmic domains homologous to those of peptide-regulated GCs. However, under the prevailing concept, its activation mechanism is significantly different from those of peptide-regulated GCs: GC-activating proteins (GCAPs) function as the sole activator of ROS-GC in a Ca(2+)-sensitive manner, and neither reception of an outside signal by the extracellular domain (ECD) nor ATP binding to the kinase homology domain (KHD) is required for its activation. We have recently shown that ATP pre-binding to the KHD in ROS-GC drastically enhances its GCAP-stimulated activity, and that rhodopsin illumination, as the outside signal, is required for the ATP pre-binding. These results indicate that illuminated rhodopsin is involved in ROS-GC activation in two ways: to initiate ATP binding to ROS-GC for preparation of its activation and to reduce [Ca(2+)] through activation of cGMP phosphodiesterase. These two signal pathways are activated in a parallel and proportional manner and finally converge for strong activation of ROS-GC by Ca(2+)-free GCAPs. These results also suggest that the ECD receives the signal for ATP binding from illuminated rhodopsin. The ECD is projected into the intradiscal space, i.e., an intradiscal domain(s) of rhodopsin is also involved in the signal transfer. Many retinal disease-linked mutations are found in these intradiscal domains; however, their consequences are often unclear. This model will also provide novel insights into causal relationship between these mutations and certain retinal diseases.
视网膜光感受器外段中的膜联型鸟苷酸环化酶(ROS-GC)是光感受器恢复到暗态的关键酶,其拓扑结构与肽调节型 GC 相同,胞质结构域与其同源。然而,根据目前的概念,其激活机制与肽调节型 GC 有显著差异:GC 激活蛋白(GCAPs)以 Ca2+敏感的方式作为 ROS-GC 的唯一激活剂,其激活不需要胞外结构域(ECD)接收外部信号,也不需要 ATP 与激酶同源结构域(KHD)结合。我们最近表明,ATP 预先结合到 ROS-GC 的 KHD 中可极大地增强其对 GCAP 的刺激活性,而光感受器的光照作为外部信号,是 ATP 预先结合所必需的。这些结果表明,受光照的视紫红质以两种方式参与 ROS-GC 的激活:启动 ROS-GC 与 ATP 的结合以准备其激活,以及通过激活 cGMP 磷酸二酯酶降低[Ca2+]。这两个信号通路以平行和比例的方式被激活,最终通过无 Ca2+的 GCAP 强烈激活 ROS-GC。这些结果还表明,ECD 从受光照的视紫红质接收与 ATP 结合相关的信号。ECD 被投射到盘内空间中,即视紫红质的盘内结构域也参与了信号传递。许多与视网膜疾病相关的突变发生在这些盘内结构域中;然而,它们的后果往往不清楚。该模型也将为这些突变与某些视网膜疾病之间的因果关系提供新的见解。