Rotin Daniela
Program in Cell Biology, The Hospital for Sick Children, and Biochemistry Department, University of Toronto, Ontario, M5G 1X8, Canada.
BMC Biochem. 2008 Oct 21;9 Suppl 1(Suppl 1):S5. doi: 10.1186/1471-2091-9-S1-S5.
Hypertension is a serious medical problem affecting a large population worldwide. Liddle syndrome is a hereditary form of early onset hypertension caused by mutations in the epithelial Na+ channel (ENaC). The mutated region, called the PY (Pro-Pro-x-Tyr) motif, serves as a binding site for Nedd4-2, an E3 ubiquitin ligase from the HECT family. Nedd4-2 binds the ENaC PY motif via its WW domains, normally leading to ENaC ubiquitylation and endocytosis, reducing the number of active channels at the plasma membrane. In Liddle syndrome, this endocytosis is impaired due to the inability of the mutated PY motif in ENaC to properly bind Nedd4-2. This leads to accumulation of active channels at the cell surface and increased Na+ (and fluid) absorption in the distal nephron, resulting in elevated blood volume and blood pressure. Small molecules/compounds that destabilize cell surface ENaC, or enhance Nedd4-2 activity in the kidney, could potentially serve to alleviate hypertension. PUBLICATION HISTORY : Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).
高血压是一个严重的医学问题，影响着全球大量人口。利德尔综合征是一种早发性高血压的遗传形式，由上皮钠通道（ENaC）突变引起。突变区域称为PY（脯氨酸-脯氨酸-x-酪氨酸）基序，作为来自HECT家族的E3泛素连接酶Nedd4-2的结合位点。Nedd4-2通过其WW结构域与ENaC PY基序结合，通常导致ENaC泛素化和内吞作用，减少质膜上活性通道的数量。在利德尔综合征中，由于ENaC中突变的PY基序无法正确结合Nedd4-2，这种内吞作用受损。这导致细胞表面活性通道的积累以及远端肾单位中钠（和液体）吸收增加，从而导致血容量和血压升高。使细胞表面ENaC不稳定或增强肾脏中Nedd4-2活性的小分子/化合物可能有助于缓解高血压。发表历史：从Current BioData的靶向蛋白质数据库（TPdb；http://www.targetedproteinsdb.com）重新发布。
