Functional Rescue of Kallmann Syndrome-associated Prokineticin Receptor 2 (PKR2) Mutants Deficient in Trafficking
Functional Rescue of Kallmann Syndrome-associated Prokineticin Receptor 2 (PKR2) Mutants Deficient in Trafficking
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功能性拯救卡尔曼综合征相关的前动力蛋白受体 2 (PKR2) 突变体缺乏运输
DOI：
10.1074/jbc.m114.556381
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发表时间：
2014-05-30
影响因子：
4.8
通讯作者：
Li, Jia-Da
中科院分区：
文献类型：
--
作者：
Chen, Dan-Na;Ma, Yan-Tao;Li, Jia-Da
已知G蛋白偶联原激动素受体2(PKR2)的突变可导致Kallmann综合征和特发性性腺激素减退症，表现为青春期延迟和不育。一些突变的受体没有被送到细胞表面；相反，它们被困在细胞分泌途径中。这些细胞特有的激动剂/拮抗剂已被用来拯救一些不针对细胞膜的膜受体。在这里，我们选择了三个与疾病相关的突变(W178S、G234D和P290S)，它们都导致了PKR2的细胞内保留。我们发现，小分子PKR2拮抗剂(A457)显著增加了细胞表面的表达，并挽救了P290S PKR2的功能，但对W178S和G234D PKR2没有影响。此外，我们还检测了化学伴侣甘油对PKR2突变体细胞表面表达和功能的影响。经10%甘油处理后，细胞表面P290S和W178S PKR2的表达和信号转导显著增加。这些数据表明，一些与Kallmann综合征相关的、细胞内保留的突变PKR2受体可以在功能上被挽救，这为携带这种突变的患者提供了一种潜在的治疗策略。
Mutations in the G protein-coupled prokineticin receptor 2 (PKR2) are known to cause Kallmann syndrome and idiopathic hypogonadotropic hypogonadism manifesting with delayed puberty and infertility. Some of the mutant receptors are not routed to the cell surface; instead, they are trapped in the cellular secretory pathway. The cell-permeant agonists/antagonists have been used to rescue some membrane receptors that are not targeted onto the cell membrane. Here, we chose three disease-associated mutations (W178S, G234D, and P290S), which all resulted in retention of PKR2 intracellularly. We show that a small molecule PKR2 antagonist (A457) dramatically increased cell surface expression and rescued the function of P290S PKR2, but had no effect on W178S and G234D PKR2. Furthermore, we also tested chemical chaperone glycerol on the cell surface expression and function of PKR2 mutants. Treatment with 10% glycerol significantly increased the cell surface expression and signaling of P290S and W178S PKR2. These data demonstrate that some Kallmann syndrome-associated, intracellularly retained mutant PKR2 receptors can be functionally rescued, suggesting a potential treatment strategy for patients bearing such mutations.