Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease.
Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease.
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OCRL 抑制肠道钙进入通道 TRPV6，OCRL 是一种与 Lowe 综合征和 Dent 病相关的脂质磷酸酶。
DOI：
10.1152/ajpcell.00277.2011
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Peng,Ji-Bin
中科院分区：
文献类型：
--
作者：
Wu,Guojin;Zhang,Wei;Na,Tao;Jing,Haiyan;Wu,Hongju;Peng,Ji-Bin
ocococerebrorenal syndrome of Lowe （OCRL）基因产物是一种磷脂酰肌醇4,5-二磷酸[PI(,)P2] 5-磷酸酶，ocl突变可导致Lowe综合征和Dent病，这两种疾病通常与高钙尿症相关。瞬时受体电位，香草蛋白亚家族，亚型6 （TRPV6）是肠上皮Ca2+通道介导活跃的Ca2+吸收。钙离子的高吸收在钙离子排泄增加的Dent病患者中被发现。在本研究中，我们使用爪蟾左卵母细胞表达系统测试了TRPV6是否受ocl调控，如果是，在多大程度上被引起凹痕的ocl突变所改变。外源性ocl通过调节TRPV6的功能和转运，通过不同的ocl结构域降低TRPV6介导的Ca2+摄取。PI(,) p25 -磷酸酶结构域可能通过调节TRPV6功能所需的PI(,) p2水平而抑制TRPV6介导的Ca2+运输，而不影响细胞表面TRPV6的TRPV6蛋白丰度。ocl可减少TRPV6的正向贩运。ocl中的Rab结合域参与调控TRPV6的转运。抑制内源性x。laevisOCRL通过反义途径增加TRPV6介导的Ca2+转运和TRPV6正向转运。所有7种引起牙凹的ocl突变都表现出对trpv6介导的Ca2+运输的抑制作用减轻，同时降低了PI(,) p25磷酸酶的总体活性。总之，ocl通过两种不同的机制抑制TRPV6。由凹痕引起的ocl突变破坏PI(,) p25磷酸酶活性可能导致肠道Ca2+吸收增加，进而导致高钙尿症。
Oculocerebrorenal syndrome of Lowe (OCRL) gene product is a phosphatidyl inositol 4,5-bisphosphate [PI(,)P2] 5-phosphatase, and mutations of OCRL cause Lowe syndrome and Dent disease, both of which are frequently associated with hypercalciuria. Transient receptor potential, vanilloid subfamily, subtype 6 (TRPV6) is an intestinal epithelial Ca2+channel mediating active Ca2+absorption. Hyperabsorption of Ca2+was found in patients of Dent disease with increased Ca2+excretion. In this study, we tested whether TRPV6 is regulated by OCRL and, if so, to what extent it is altered by Dent-causing OCRL mutations usingXenopus laevisoocyte expression system. Exogenous OCRL decreased TRPV6-mediated Ca2+uptake by regulating the function and trafficking of TRPV6 through different domains of OCRL. The PI(,)P25-phosphatase domain suppressed the TRPV6-mediated Ca2+transport likely through regulating the PI(,)P2level needed for TRPV6 function without affecting TRPV6 protein abundance of TRPV6 at the cell surface. The forward trafficking of TRPV6 was decreased by OCRL. The Rab binding domain in OCRL was involved in regulating the trafficking of TRPV6. Knocking down endogenousX. laevisOCRL by antisense approach increased TRPV6-mediated Ca2+transport and TRPV6 forward trafficking. All seven Dent-causing OCRL mutations examined exhibited alleviation of the inhibitory effect on TRPV6-mediated Ca2+transport together with decreased overall PI(,)P25-phosphatase activity. In conclusion, OCRL suppresses TRPV6 via two separate mechanisms. The disruption of PI(,)P25-phosphatase activity by Dent-causing mutations of OCRL may lead to increased intestinal Ca2+absorption and, in turn, hypercalciuria.
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