Function and regulation of TRPP2 at the plasma membrane.
Function and regulation of TRPP2 at the plasma membrane.
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DOI：
10.1152/ajprenal.90277.2008
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发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
L. Tsiokas
中科院分区：
文献类型：
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作者：
L. Tsiokas
在所有已知的常染色体显性多囊肾病（ADPKD）病例中，绝大多数（约99%）是由两个独立但遗传相互作用的基因座pkd 1和pkd 2中的天然突变引起的。pkd 1编码一种功能未知的大的多跨膜蛋白（PKD 1），而pkd 2编码离子通道的瞬时受体电位（TRP）超家族的蛋白（TRPP 2、多囊蛋白-2或PKD 2）。生物化学，功能和遗传学研究支持PKD 1与TRPP 2物理相互作用形成离子通道复合物，将细胞外刺激传递到离子电流的模型。然而，这些细胞外刺激的分子身份仍然难以捉摸。细胞培养中的功能研究表明，TRPP 2可以响应于细胞表面的机械信号（流体剪切应力）和/或受体酪氨酸激酶（RTK）和G蛋白偶联受体（GPCR）活化而被活化。最近对莱茵衣藻的遗传学研究表明，CrPKD 2在连接细胞间粘附和Ca（2+）信号传导的途径中发挥作用。激活模式取决于与其他通道亚基和辅助蛋白的蛋白质-蛋白质相互作用。因此，了解TRPP 2复合物的分子组成的机制对于描述TRPP 2激活的机制至关重要，最重要的是，自然发生的pkd 1或pkd 2突变不仅导致ADPKD，而且导致缺乏功能性TRPP 2的模型生物体中报告的其他缺陷的机制。本文综述了TRPP 2作为细胞表面阳离子通道的分子组装、功能和调控，并讨论了其在Ca（2+）信号转导和ADPKD病理生理中的潜在作用。
The vast majority (approximately 99%) of all known cases of autosomal dominant polycystic kidney disease (ADPKD) are caused by naturally occurring mutations in two separate, but genetically interacting, loci, pkd1 and pkd2. pkd1 encodes a large multispanning membrane protein (PKD1) of unknown function, while pkd2 encodes a protein (TRPP2, polycystin-2, or PKD2) of the transient receptor potential (TRP) superfamily of ion channels. Biochemical, functional, and genetic studies support a model in which PKD1 physically interacts with TRPP2 to form an ion channel complex that conveys extracellular stimuli to ionic currents. However, the molecular identity of these extracellular stimuli remains elusive. Functional studies in cell culture show that TRPP2 can be activated in response to mechanical cues (fluid shear stress) and/or receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR) activation at the cell surface. Recent genetic studies in Chlamydomonas reinhardtii show that CrPKD2 functions in a pathway linking cell-cell adhesion and Ca(2+) signaling. The mode of activation depends on protein-protein interactions with other channel subunits and auxiliary proteins. Therefore, understanding the mechanisms underlying the molecular makeup of TRPP2-containing complexes is critical in delineating the mechanisms of TRPP2 activation and, most importantly, the mechanisms by which naturally occurring mutations in pkd1 or pkd2 lead not only to ADPKD, but also to other defects reported in model organisms lacking functional TRPP2. This review focuses on the molecular assembly, function, and regulation of TRPP2 as a cell surface cation channel and discusses its potential role in Ca(2+) signaling and ADPKD pathophysiology.