Pharmacological modulation of diacylglycerol-sensitive TRPC3/6/7 channels.
Pharmacological modulation of diacylglycerol-sensitive TRPC3/6/7 channels.
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DOI：
10.2174/138920111793937943
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发表时间：
2011-01-01
影响因子：
2.8
通讯作者：
Gollasch M
中科院分区：
文献类型：
--
作者：
Harteneck C;Gollasch M
经典类型的瞬时受体电位通道（TRPC）的成员代表参与激素信号转导的重要分子。TRPC 3/6/7通道是特别感兴趣的，因为它们是磷脂酶C驱动的信号传导途径的组分。在受体活化后，G蛋白介导的磷脂酶C刺激导致磷脂酰肌醇分解，导致细胞内二酰基甘油和肌醇三磷酸水平增加。甘油二酯激活蛋白激酶C，但更有趣的是甘油二酯直接激活TRPC 2/3/6/7通道。TRP通道的分子克隆、表达和表征使得受体依赖性钙离子进入的传统抑制剂如SKF-96365和2-APB能够重新分配为TRPC 3/6/7和非经典TRP通道的几个成员的阻断剂。此外，几种酶抑制剂也被鉴定为TRP通道阻断剂，如ACA，磷脂酶A2抑制剂，和W-7，钙调蛋白拮抗剂。最后，天然存在的次生植物化合物贯叶金丝桃素已被确定为TRPC 6选择性药物，提供了一个令人兴奋的概念证明，它是可能产生TRPC选择性通道调节剂。Pyr 3作为第一个TRPC 3选择性抑制剂的描述表明，不仅自然界，而且人类能够产生TRP选择性调节剂。该审查揭示了TRPC 3/6/7的药理学调节剂的当前知识和历史发展。我们的分析表明，Pyr 3和贯叶金丝桃素为开发新的、选择性的和更有效的TRPC 3/6/7活性调节剂提供了有前途的核心结构。
Members of the classic type of transient receptor potential channels (TRPC) represent important molecules involved in hormonal signal transduction. TRPC3/6/7 channels are of particular interest as they are components of phospholipase C driven signalling pathways. Upon receptor-activation, G-protein-mediated stimulation of phospholipase C results in breakdown of phosphatidylinositides leading to increased intracellular diacylglycerol and inositol-trisphosphate levels. Diacylglycerol activates protein kinase C, but more interestingly diacylglycerol directly activates TRPC2/3/6/7 channels. Molecular cloning, expression and characterization of TRP channels enabled reassignment of traditional inhibitors of receptor-dependent calcium entry such as SKF-96365 and 2-APB as blockers of TRPC3/6/7 and several members of non-classic TRP channels. Furthermore, several enzyme inhibitors have also been identified as TRP channel blockers, such as ACA, a phospholipase A2 inhibitor, and W-7, a calmodulin antagonist. Finally, the naturally occurring secondary plant compound hyperforin has been identified as TRPC6-selective drug, providing an exciting proof of concept that it is possible to generate TRPC-selective channel modulators. The description of Pyr3 as the first TRPC3-selective inhibitor shows that not only nature but also man is able to generate TRP-selective modulators. The review sheds lights on the current knowledge and historical development of pharmacological modulators of TRPC3/6/7. Our analysis indicates that Pyr3 and hyperforin provide promising core structures for the development of new, selective and more potent modulators of TRPC3/6/7 activity.
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影响因子：
64.8
作者：
Chyb, S;Raghu, P;Hardie, RC
通讯作者：
Hardie, RC
影响因子：
6.5
作者：
Beck, Benjamin;Zholos, Alexander;Skryma, Roman
通讯作者：
Skryma, Roman
影响因子：
5.3
作者：
Dietrich, A;Schnitzler, MMY;Birnbaumer, L
通讯作者：
Birnbaumer, L
影响因子：
5.3
作者：
Chung, MK;Lee, H;Caterina, MJ
通讯作者：
Caterina, MJ
影响因子：
5.5
作者：
Jung, S;Strotmann, R;Plant, TD
通讯作者：
Plant, TD