Lu Boxun, Su Yanhua, Das Sudipto, Wang Haikun, Wang Yan, Liu Jin, Ren Dejian
Department of Biology, University of Pennsylvania, 415 S. University Avenue, Philadelphia, Pennsylvania 19104, USA.
Nature. 2009 Feb 5;457(7230):741-4. doi: 10.1038/nature07579. Epub 2008 Dec 17.
Several neurotransmitters act through G-protein-coupled receptors to evoke a 'slow' excitation of neurons. These include peptides, such as substance P and neurotensin, as well as acetylcholine and noradrenaline. Unlike the fast (approximately millisecond) ionotropic actions of small-molecule neurotransmitters, the slow excitation is not well understood at the molecular level, but can be mainly attributed to suppressing K(+) currents and/or activating a non-selective cation channel. The molecular identity of this cation channel has yet to be determined; similarly, how the channel is activated and its relative contribution to neuronal excitability induced by the neuropeptides are unknown. Here we show that, in the mouse hippocampal and ventral tegmental area neurons, substance P and neurotensin activate a channel complex containing NALCN and a large previously unknown protein UNC-80. The activation by substance P through TACR1 (a G-protein-coupled receptor for substance P) occurs by means of a unique mechanism: it does not require G-protein activation but is dependent on Src family kinases. These findings identify NALCN as the cation channel activated by substance P receptor, and suggest that UNC-80 and Src family kinases, rather than a G protein, are involved in the coupling from receptor to channel.
几种神经递质通过G蛋白偶联受体发挥作用，引发神经元的“缓慢”兴奋。这些神经递质包括肽类，如P物质和神经降压素，以及乙酰胆碱和去甲肾上腺素。与小分子神经递质的快速（约毫秒级）离子otropic作用不同，这种缓慢兴奋在分子水平上尚未得到很好的理解，但主要可归因于抑制钾离子电流和/或激活非选择性阳离子通道。该阳离子通道的分子身份尚未确定；同样，该通道如何被激活以及它对神经肽诱导的神经元兴奋性的相对贡献也不清楚。在这里，我们表明，在小鼠海马体和腹侧被盖区神经元中，P物质和神经降压素激活了一个包含NALCN和一种此前未知的大蛋白UNC-80的通道复合物。P物质通过TACR1（P物质的一种G蛋白偶联受体）的激活通过一种独特的机制发生：它不需要G蛋白激活，但依赖于Src家族激酶。这些发现确定NALCN为被P物质受体激活的阳离子通道，并表明UNC-80和Src家族激酶，而非G蛋白，参与了从受体到通道的偶联。
