Role of PDZK1 Protein in Apical Membrane Expression of Renal Sodium-coupled Phosphate Transporters
Role of PDZK1 Protein in Apical Membrane Expression of Renal Sodium-coupled Phosphate Transporters
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DOI：
10.1074/jbc.m110.199752
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发表时间：
2011-04-29
影响因子：
4.8
通讯作者：
Levi, Moshe
中科院分区：
文献类型：
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作者：
Giral, Hector;Lanzano, Luca;Levi, Moshe
钠依赖的磷酸(Na/P-I)转运体napi-2a和napi-2c在P-I的肾重吸收中起主要作用。几个转运体完成相同角色的功能需求仍然不清楚。然而，这些转运蛋白在饮食和激素刺激下表现出不同的调节，这一事实表明，这些转运蛋白在P-I重吸收中扮演不同的角色。控制这种差异调控的途径尚不清楚，但参与其中的候选基因之一是支架PDZ蛋白的NHERF家族。我们认为，与PDZ蛋白分子相互作用的差异与Na/P-I转运蛋白的差异适应有关。适应长期低P-I饮食的Pdzk1(-/-)小鼠近端小管顶膜Napi-2a蛋白表达增加，但对Napi-2c的上调作用减弱。这些结果表明，PDZK1在稳定Napi-2c在根尖膜中起重要作用。我们用FRET研究了Na/P-I转运蛋白与NHERF-1和PDZK1的特异性蛋白-蛋白相互作用。FRET测量表明NHERF-1与Napi-2a的相互作用比与Napi-2c的作用强得多。然而，两个Na/P-I转运体与PDZK1显示出相似的FRET效率。有趣的是，在适应低P-I浓度的细胞中，Napi-2c/PDZK1和Napi-2a/NHERF-1的相互作用增加。Na/P-I转运蛋白对NHERF-1和PDZK1蛋白的不同亲和力可以部分解释它们在顶膜上的不同调节和/或稳定性。在这一点上，Napi-2c与PDZK1之间的直接相互作用似乎在Napi-2c的生理调节中发挥了重要作用。
The sodium-dependent phosphate (Na/P-i) transporters NaPi-2a and NaPi-2c play a major role in the renal reabsorption of P-i. The functional need for several transporters accomplishing the same role is still not clear. However, the fact that these transporters show differential regulation under dietary and hormonal stimuli suggests different roles in P-i reabsorption. The pathways controlling this differential regulation are still unknown, but one of the candidates involved is the NHERF family of scaffolding PDZ proteins. We propose that differences in the molecular interaction with PDZ proteins are related with the differential adaptation of Na/P-i transporters. Pdzk1(-/-) mice adapted to chronic low P-i diets showed an increased expression of NaPi-2a protein in the apical membrane of proximal tubules but impaired up-regulation of NaPi-2c. These results suggest an important role for PDZK1 in the stabilization of NaPi-2c in the apical membrane. We studied the specific protein-protein interactions of Na/P-i transporters with NHERF-1 and PDZK1 by FRET. FRET measurements showed a much stronger interaction of NHERF-1 with NaPi-2a than with NaPi-2c. However, both Na/P-i transporters showed similar FRET efficiencies with PDZK1. Interestingly, in cells adapted to low P-i concentrations, there were increases in NaPi-2c/PDZK1 and NaPi-2a/NHERF-1 interactions. The differential affinity of the Na/P-i transporters for NHERF-1 and PDZK1 proteins could partially explain their differential regulation and/or stability in the apical membrane. In this regard, direct interaction between NaPi-2c and PDZK1 seems to play an important role in the physiological regulation of NaPi-2c.