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首页> 外文期刊>American Journal of Physiology >Nonsynonymous single nucleotide polymorphisms of NHE3 differentially decrease NHE3 transporter activity
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Nonsynonymous single nucleotide polymorphisms of NHE3 differentially decrease NHE3 transporter activity

机译：NHE3差异降低NHE3转运蛋白活性的非纯单核苷酸多态性

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Genetic determinants appear to play a role in susceptibility to chronic diarrhea;, but the genetic abnormalities involved have only been identified in a few conditions. The Na+/H+ exchanger 3 (NHE3) accounts for a large fraction of physiologic intestinal Na+ absorption. It is highly regulated through effects on its intracellular COOH-terminal regulatory domain. The impact of genetic variation in the NHE3 gene, such as single nucleotide polymorphisms (SNPs), on transporter activity remains unexplored. From a total of 458 SNPs identified in the entire NHE3 gene, we identified three nonsynonymous mutations (R474Q, V567M, and R799C), which were all in the protein's intracellular COOH-terminal domain. Here we evaluated whether these SNPs affect NHE3 activity by expressing them in a mammalian cell line that is null for all plasma membrane NHEs. These variants significantly reduced basal NHE3 transporter activity through a reduction in intrinsic NHE3 function in variant R474Q, abnormal trafficking in variant V567M, or defects in both intrinsic NHE3 function and trafficking in variant R799C. In addition, variants NHE3 R474Q and R799C failed to respond to acute dexamethasone stimulation, suggesting cells with these mutant proteins might be defective in NHE3 function during postprandial stimulation and perhaps under stressful conditions. Finally, variant R474Q was shown to exhibit an aberrant interaction with calcineurin B homologous protein (CHP), an NHE3 regulatory protein required for basal NHE3 activity. Taken together, these results demonstrate decreased transport activity in three SNPs of NHE3 and provide mechanistic insight into how these SNPs impact NHE3 function.
机译：遗传决定簇似乎在对慢性腹泻的易感性中发挥作用;但只有在一些条件下才发现所涉及的遗传异常。 Na + / H +交换器3（NHE3）占大部分的生理肠道Na +吸收。它受到对细胞内CoOH末端调节结构域的影响。在转运蛋白活动中，NHE3基因（例如单核苷酸多态性（SNP）等单核苷酸活性的遗传变异的影响仍未探索。在整个NHE3基因中鉴定的总共458个SNP，我们确定了三种非唯一突变（R474Q，V567M和R799C），全部都在蛋白质的细胞内核末端结构域中。在这里，我们通过在哺乳动物细胞系中表达它们为所有浆膜核核表达，评估这些SNP是否会影响NHE3活性。这些变体通过变体R474Q中的内在NHE3功能，变体V567M异常的血管型，或缺陷在型NHE3功能和贩运变体R799C中的缺陷，显着降低了基础NHE3转运蛋白活性。此外，变体NHE3 R474Q和R799C未能应对急性地塞米松刺激，表明具有这些突变蛋白的细胞在后刺激期间在NHE3功能中可能存在缺陷，并且可能在压力条件下可能存在缺陷。最后，显示变体R474Q与钙磷素B同源蛋白（CHP）的异常相互作用，基于NHE3活性所需的NHE3调节蛋白。总之，这些结果表明，在NHE3的三个SNP中展示了运输活性减少，并为这些SNPS冲击的机械洞察提供了机械洞察NHE3功能。

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