Mederos Y Schnitzler Michael, Gudermann Thomas, Storch Ursula
Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilians University of Munich, 80336 Munich, Germany.
DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, 80802 Munich, Germany.
Cells. 2018 Nov 20;7(11):218. doi: 10.3390/cells7110218.
Transient receptor potential classical or canonical 4 (TRPC4) and TRPC5 channels are members of the classical or canonical transient receptor potential (TRPC) channel family of non-selective cation channels. TRPC4 and TRPC5 channels are widely accepted as receptor-operated cation channels that are activated in a phospholipase C-dependent manner, following the G protein-coupled receptor activation. However, their precise activation mechanism has remained largely elusive for a long time, as the TRPC4 and TRPC5 channels were considered as being insensitive to the second messenger diacylglycerol (DAG) in contrast to the other TRPC channels. Recent findings indicate that the C-terminal interactions with the scaffolding proteins Na⁺/H⁺ exchanger regulatory factor 1 and 2 (NHERF1 and NHERF2) dynamically regulate the DAG sensitivity of the TRPC4 and TRPC5 channels. Interestingly, the C-terminal NHERF binding suppresses, while the dissociation of NHERF enables, the DAG sensitivity of the TRPC4 and TRPC5 channels. This leads to the assumption that all of the TRPC channels are DAG sensitive. The identification of the regulatory function of the NHERF proteins in the TRPC4/5-NHERF protein complex offers a new starting point to get deeper insights into the molecular basis of TRPC channel activation. Future studies will have to unravel the physiological and pathophysiological functions of this multi-protein channel complex.
瞬时受体电位经典或标准型4（TRPC4）通道和TRPC5通道是非选择性阳离子通道的经典或标准型瞬时受体电位（TRPC）通道家族的成员。TRPC4通道和TRPC5通道被广泛认为是受体操纵的阳离子通道，在G蛋白偶联受体激活后，以磷脂酶C依赖的方式被激活。然而，它们的确切激活机制在很长一段时间内仍基本不清楚，因为与其他TRPC通道相比，TRPC4通道和TRPC5通道被认为对第二信使二酰基甘油（DAG）不敏感。最近的研究结果表明，与支架蛋白钠/氢交换调节因子1和2（NHERF1和NHERF2）的C端相互作用动态调节TRPC4通道和TRPC5通道的DAG敏感性。有趣的是，C端与NHERF的结合会抑制TRPC4通道和TRPC5通道的DAG敏感性，而NHERF的解离则会使其激活。这导致人们推测所有的TRPC通道对DAG都敏感。NHERF蛋白在TRPC4/5-NHERF蛋白复合物中的调节功能的确定为更深入了解TRPC通道激活的分子基础提供了一个新的起点。未来的研究将不得不阐明这种多蛋白通道复合物的生理和病理生理功能。
