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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >RD3, the protein associated with Leber congenital amaurosis type 12, is required for guanylate cyclase trafficking in photoreceptor cells
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RD3, the protein associated with Leber congenital amaurosis type 12, is required for guanylate cyclase trafficking in photoreceptor cells

机译：RD3是与Leber 12型先天性黑蒙症相关的蛋白质，是感光细胞中鸟苷酸环化酶运输所必需的

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摘要

Guanylate cyclases, GC1 and GC2, are localized in the light-sensitive outer segment compartment of photoreceptor cells, where they play a crucial role in phototransduction by catalyzing the synthesis of cGMP, the second messenger of phototransduction, and regulating intracellular Ca~(2+) levels in combination with the cGMP-gated channel. Mutations in GC1 are known to cause Leber congenital amaurosis type 1 (LCA1), a childhood disease associated with severe vision loss. Although the enzymatic and regulatory properties of guanylate cyclases have been studied extensively, the molecular determinants responsible for their trafficking in photoreceptors remain unknown. Here we show that RD3, a protein of unknown function encoded by a gene associated with photoreceptor degeneration in humans with Leber congenital amaurosis type 12 (LCA12), the rd3 mouse, and rcd2 collie, colocalizes and interacts with GC1 and GC2 in rod and cone photoreceptor cells of normal mice. GC1 and GC2 are undetectable in photoreceptors of the rd3 mouse deficient in RD3 by immunofluorescence microscopy. Cell expression studies show that RD3 mediates the export of GC1 from the endoplasmic reticulum to endosomal vesicles, and that the C terminus of GC1 is required for RD3 binding. Our results indicate that photoreceptor degeneration in the rd3 mouse, rcd2 dog, and LCA12 patients is caused by impaired RD3-mediated guanylate cyclase expression and trafficking. The resulting deficiency in cGMP synthesis and the constitutive closure of cGMP-gated channels might cause a reduction in intracellular Ca~(2+) to a level below that required for long-term photoreceptor cell survival.
机译：鸟苷酸环化酶GC1和GC2定位在感光细胞的感光外段区室中，在那里它们通过催化cGMP的合成在光转导中起关键作用，cGMP是光转导的第二信使，并调节细胞内Ca〜（2+ ）水平与cGMP门控通道结合使用。已知GC1中的突变会导致Leber 1型先天性黑蒙症（LCA1），这是一种与严重视力丧失有关的儿童疾病。尽管已经广泛研究了鸟苷酸环化酶的酶促和调节特性，但负责其转运光受体的分子决定因素仍然未知。在这里，我们显示RD3（一种功能未知的蛋白质，由与Leber先天性黑蒙12型（LCA12），rd3小鼠和rcd2牧羊犬的人的感光器变性相关的基因编码，与杆和锥中的GC1和GC2共定位并相互作用）正常小鼠的感光细胞。通过免疫荧光显微镜检查，在RD3缺陷的rd3小鼠的感光器中无法检测到GC1和GC2。细胞表达研究表明RD3介导了GC1从内质网向内体囊泡的输出，并且RD3结合需要GC1的C末端。我们的结果表明，rd3小鼠，rcd2狗和LCA12患者中的感光细胞变性是由RD3介导的鸟苷酸环化酶表达和运输受损引起的。导致的cGMP合成不足和cGMP门控通道的组成性关闭可能导致细胞内Ca〜（2+）降低至低于长期光感受器细胞存活所需的水平。

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