The A563T variation of the renal epithelial calcium channel TRPV5 among African Americans enhances calcium influx
The A563T variation of the renal epithelial calcium channel TRPV5 among African Americans enhances calcium influx
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DOI：
10.1152/ajprenal.90771.2008
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发表时间：
2009-05-01
影响因子：
4.2
通讯作者：
Peng, Ji-Bin
中科院分区：
文献类型：
--
作者：
Na, Tao;Zhang, Wei;Peng, Ji-Bin
Na T，Zhang W，Jiang Y，Liang Y，Ma H，Warnock DG，Peng J。非洲裔美国人中肾上皮钙通道 TRPV5 的 A563T 变异增强了钙流入。 Am J Physiol Renal Physiol 296：F1042-F1051，2009。首次发表于 2009 年 3 月 4 日； doi:10.1152/ajprenal.90771.2008.-瞬时受体电位阳离子通道、亚科 V、成员 5 (TRPV5) 基因编码肾远曲小管和连接小管顶膜中的 Ca2+ 通道，在非裔美国人中表现出异常高频率的非同义单核苷酸多态性 (SNP)。为了评估 TRPV5 中非同义 SNP 变异的功能影响，使用放射性示踪剂 Ca-45(2+) 流入测定和使用非洲爪蟾卵母细胞的电压钳技术对这些变异进行了分析。在测试的变异中，包括A8V、R154H、A563T和L712F，后两者显着增加了TRPV5介导的Ca2+流入。 A563T 变体在非裔美国人中存在的频率相对较高，尽管在质膜上的表达水平较低，但细胞外 Ca2+ 的 Ca2+ 流入量从 0.01 mM 增加到 2 mM。由于对细胞外 Mg2+ 的敏感性增加，该变体还表现出 Na+ 电流的减少。通过用丝氨酸或缬氨酸残基取代苏氨酸 563 (Thr(563))，Thr(563) 的庞大侧链被证明可以促进 Ca2+ 转运，而 Thr(563) 的羟基可能与 Mg2+ 敏感性有关。 A563T 变体能够增加 TRPV5 介导的 Ca2+ 流入，即使它是在与其他变体模拟杂合或复合状态的条件下表达的。总之，TRPV5 的 A563T 变体通过影响 Ca2+ 渗透途径显着增加 Ca2+ 内流。因此，TRPV5 中的 A563T 变异可能有助于非裔美国人肾脏保存 Ca2+ 的能力更强。
Na T, Zhang W, Jiang Y, Liang Y, Ma H, Warnock DG, Peng J. The A563T variation of the renal epithelial calcium channel TRPV5 among African Americans enhances calcium influx. Am J Physiol Renal Physiol 296: F1042-F1051, 2009. First published March 4, 2009; doi:10.1152/ajprenal.90771.2008.-The transient receptor potential cation channel, subfamily V, member 5 (TRPV5) gene, which encodes the Ca2+ channel in the apical membrane of distal convoluted tubule and connecting tubule of the kidney, exhibits an unusually high frequency of nonsynonymous single nucleotide polymorphisms (SNPs) among African Americans. To assess the functional impacts of the nonsynonymous SNP variations in TRPV5, these variants were analyzed with radiotracer Ca-45(2+) influx assay and the voltage-clamp technique using Xenopus laevis oocytes. Among the variations tested, including A8V, R154H, A563T, and L712F, the latter two significantly increased TRPV5-mediated Ca2+ influx. The A563T variant, which exists in African Americans with relative high frequency, exhibited increased Ca2+ influx at extracellular Ca2+ from 0.01 to 2 mM despite a lower expression level at the plasma membrane. This variant also exhibited a reduction in Na+ current as a result of increased sensitivity to extracellular Mg2+. By substituting threonine-563 (Thr(563)) with serine or valine residue, the bulky side chain of Thr(563) was shown to facilitate Ca2+ transport, whereas the hydroxyl group of Thr(563) is likely related to Mg2+ sensitivity. The A563T variant was capable of increasing TRPV5-mediated Ca2+ influx, even when it was expressed under conditions mimicking heterozygous or compound state with other variants. In conclusion, the A563T variant of TRPV5 significantly increased Ca2+ influx by affecting the Ca2+ permeation pathway. Thus the A563T variation in TRPV5 may contribute to the superior ability of renal Ca2+ conservation in African Americans.