Hofmann T, Obukhov A G, Schaefer M, Harteneck C, Gudermann T, Schultz G
Institut für Pharmakologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Germany.
Nature. 1999 Jan 21;397(6716):259-63. doi: 10.1038/16711.
Eukaryotic cells respond to many hormones and neurotransmitters with increased activity of the enzyme phospholipase C and a subsequent rise in the concentration of intracellular free calcium ([Ca2+]i). The increase in [Ca2+]i occurs as a result of the release of Ca2+ from intracellular stores and an influx of Ca2+ through the plasma membrane; this influx of Ca2+ may or may not be store-dependent. Drosophila transient receptor potential (TRP) proteins and some mammalian homologues (TRPC proteins) are thought to mediate capacitative Ca2+ entry. Here we describe the molecular mechanism of store-depletion-independent activation of a subfamily of mammalian TRPC channels. We find that hTRPC6 is a non-selective cation channel that is activated by diacylglycerol in a membrane-delimited fashion, independently of protein kinases C activated by diacylglycerol. Although hTRPC3, the closest structural relative of hTRPC6, is activated in the same way, TRPCs 1, 4 and 5 and the vanilloid receptor subtype 1 are unresponsive to the lipid mediator. Thus, hTRPC3 and hTRPC6 represent the first members of a new functional family of second-messenger-operated cation channels, which are activated by diacylglycerol.
真核细胞对许多激素和神经递质的反应是磷脂酶C的活性增加，随后细胞内游离钙浓度（[Ca2+]i）上升。[Ca2+]i的增加是由于细胞内钙库释放Ca2+以及Ca2+通过质膜内流所致；这种Ca2+内流可能依赖也可能不依赖于钙库。果蝇瞬时受体电位（TRP）蛋白和一些哺乳动物同源物（TRPC蛋白）被认为介导了钙库调控的Ca2+内流。在此，我们描述了哺乳动物TRPC通道亚家族不依赖于钙库耗竭的激活分子机制。我们发现hTRPC6是一种非选择性阳离子通道，它以膜限定的方式被二酰基甘油激活，与二酰基甘油激活的蛋白激酶C无关。尽管hTRPC6最接近的结构相关物hTRPC3也以同样的方式被激活，但TRPC1、4和5以及香草酸受体亚型1对这种脂质介质无反应。因此，hTRPC3和hTRPC6代表了一类新的由第二信使操作的阳离子通道功能家族的首批成员，它们被二酰基甘油激活。
