Targeting the regulation of CFTR channels.
Targeting the regulation of CFTR channels.
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DOI：
10.1042/bj20110461
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发表时间：
2011-04-15
期刊：
影响因子：
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通讯作者：
Bear, Christine E
中科院分区：
文献类型：
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作者：
Eckford, Paul D W;Bear, Christine E
Zhang等人在这期的《生化杂志》上揭示了一种新的策略，可以修改上皮细胞顶端表面的CFTR（囊性纤维化跨膜传导调节因子）的调节功能。简单地说，这些作者测试了这样一种观点，即CFTR的cAMP依赖通道活性可以通过破坏通常抑制cAMP产生的蛋白质-蛋白质相互作用而有效增强。这种特殊的蛋白-蛋白相互作用[在LPA2（2型溶血磷脂酸受体）的PDZ基序和支架蛋白Nherf2 （Na+/H+交换调节因子2）之间]定位于上皮细胞顶膜上的CFTR相互作用组。因此，LPA2-Nherf2相互作用的破坏应导致cAMP的局部升高，从而增加上皮细胞表面cAMP依赖的CFTR活性。Zhang等人利用被认为可以模拟人类呼吸上皮的相关培养物和组织，证实了针对LPA2-Nherf2相互作用的小分子化合物的这些期望。这一策略的成功取决于先前关于多个pdz基序介导的相互作用在（直接或间接）向CFTR信号传导中的作用的知识。考虑到pdz介导的相互作用的数量和多样性，未来的结构和计算研究将对指导特定药物干预的设计至关重要。
In this issue of the Biochemical Journal, Zhang et al. reveal a new strategy for modifying the regulated function of CFTR (cystic fibrosis transmembrane conductance regulator) on the apical surface of epithelial cells. Simply stated, these authors tested the idea that the cAMP-dependent channel activity of CFTR could be effectively enhanced by disruption of a protein-protein interaction which is normally inhibitory for the production of cAMP. This particular protein-protein interaction [between the PDZ motif of LPA2 (type 2 lysophosphatidic acid receptor) and the scaffold protein Nherf2 (Na+/H+ exchanger regulatory factor 2)] is localized in the CFTR interactome on the apical membrane of epithelial cells. Hence disruption of the LPA2-Nherf2 interaction should lead to a localized elevation in cAMP and, consequently, increased cAMP-dependent CFTR activity on the surface of epithelial cells. Zhang et al. confirmed these expectations for a small-molecule compound targeting the LPA2-Nherf2 interaction using relevant cultures and tissues thought to model the human respiratory epithelium. The success of this strategy depended on previous knowledge regarding the role for multiple PDZ-motif-mediated interactions in signalling (directly or indirectly) to CFTR. Given the number and diversity of such PDZ-mediated interactions, future structural and computational studies will be essential for guiding the design of specific pharmacological interventions.