Regulation of the epithelial Ca²⁺ channel TRPV5 by reversible histidine phosphorylation mediated by NDPK-B and PHPT1.
Regulation of the epithelial Ca²⁺ channel TRPV5 by reversible histidine phosphorylation mediated by NDPK-B and PHPT1.
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DOI：
10.1091/mbc.e13-04-0180
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发表时间：
2014-04
影响因子：
3.3
通讯作者：
Skolnik EY
中科院分区：
文献类型：
--
作者：
Cai X;Srivastava S;Surindran S;Li Z;Skolnik EY
TRPV5和Ca~(2+)被肾脏重吸收是一种新的调节机制。这支持了组氨酸磷酸化在哺乳动物生物学中发挥其他尚未被发现的作用的观点。肾与骨和肠一起，在维持全身钙平衡方面起着至关重要的作用，这主要是通过改变肾小球过滤的钙的重吸收来实现的。瞬时受体电位-香草酸-5(TRPV5)通道蛋白形成一个六跨膜钙离子通透通道，通过介导肾脏远端曲管对钙的主动重吸收来调节尿钙的排泄。在这里，我们证明了组氨酸激酶，二磷酸核苷激酶B(NDPK-B)，激活了TRPV5通道的活性和钙离子流量，这种激活需要在TRPV5的羧基末端的组氨酸711。此外，组氨酸磷酸酶，蛋白质组氨酸磷酸酶1，在内外贴片实验中抑制NDPK-B激活的TRPV5。这在生理上与体内钙的重吸收有关，因为NDPK-B的短发夹状RNA敲除导致TRPV5通道活性降低，而喂食高钙饮食的NDPK-B−/−小鼠尿钙排泄增加。因此，这些发现确定了一种新的机制，即TRPV5和Ca~(2+)重吸收由肾脏调节，并支持组氨酸磷酸化在哺乳动物生物学中发挥其他尚未被发现的作用的想法。
A novel mechanism is shown by which TRPV5 and Ca2+ reabsorption by the kidney is regulated. This supports the idea that histidine phosphorylation plays other, yet-uncovered roles in mammalian biology. The kidney, together with bone and intestine, plays a crucial role in maintaining whole-body calcium (Ca2+) homoeostasis, which is primarily mediated by altering the reabsorption of Ca2+ filtered by the glomerulus. The transient receptor potential-vanilloid-5 (TRPV5) channel protein forms a six- transmembrane Ca2+-permeable channel that regulates urinary Ca2+ excretion by mediating active Ca2+ reabsorption in the distal convoluted tubule of the kidney. Here we show that the histidine kinase, nucleoside diphosphate kinase B (NDPK-B), activates TRPV5 channel activity and Ca2+ flux, and this activation requires histidine 711 in the carboxy-terminal tail of TRPV5. In addition, the histidine phosphatase, protein histidine phosphatase 1, inhibits NDPK-B–activated TRPV5 in inside/out patch experiments. This is physiologically relevant to Ca2+ reabsorption in vivo, as short hairpin RNA knockdown of NDPK-B leads to decreased TRPV5 channel activity, and urinary Ca2+ excretion is increased in NDPK-B−/− mice fed a high-Ca2+ diet. Thus these findings identify a novel mechanism by which TRPV5 and Ca2+ reabsorption is regulated by the kidney and support the idea that histidine phosphorylation plays other, yet-uncovered roles in mammalian biology.