Protection of TRPC7 cation channels from calcium inhibition by closely associated SERCA pumps
Protection of TRPC7 cation channels from calcium inhibition by closely associated SERCA pumps
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DOI：
10.1096/fj.05-4714fje
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发表时间：
2006-01-01
期刊：
影响因子：
4.8
通讯作者：
Putney, JW
中科院分区：
文献类型：
--
作者：
Lemonnier, L;Trebak, M;Putney, JW
大量研究表明，瞬时受体电位(Trp)超家族的成员参与了钙离子内流的调节。此外，大多数钙离子通透通道本身都受到钙离子的调节，通常是以复杂的方式进行的。在目前的研究中，我们研究了TRPC7的调节，一个已知可能被商店操作的机制和涉及二酰甘油的非商店操作的机制激活的通道。令人惊讶的是，我们发现二酰甘油激活TRPC7通道可被SERCA泵抑制剂thapsigargin阻断。结构上相关的通道TRPC3也同样被抑制。这种作用依赖于细胞外钙离子和钙离子内流的驱动力。这种抑制不是由于钙通过商店操作的通道进入，而是由于钙通过TRPC7通道本身进入。Thapsigargin的作用可通过抑制钙调蛋白来阻止，并可通过药物破坏肌动蛋白细胞骨架来模拟。我们的结果表明，存在一种新的机制，涉及通过钙进入TRPC通道而对该通道进行负调节。在生理条件下，钙的这种负反馈会被密切相关的SERCA泵的存在所减弱。
Numerous studies have demonstrated that members of the transient receptor potential (TRP) superfamily of channels are involved in regulated Ca2+ entry. Additionally, most Ca2+-permeable channels are themselves regulated by Ca2+, often in complex ways. In the current study, we have investigated the regulation of TRPC7, a channel known to be potentially activated by both store-operated mechanisms and non-store-operated mechanisms involving diacylglycerols. Surprisingly, we found that activation of TRPC7 channels by diacylglycerol was blocked by the SERCA pump inhibitor thapsigargin. The structurally related channel, TRPC3, was similarly inhibited. This effect depended on extracellular calcium and on the driving force for Ca2+ entry. The inhibition is not due to calcium entry through store-operated channels but rather results from calcium entry through TRPC7 channels themselves. The effect of thapsigargin was prevented by inhibition of calmodulin and was mimicked by pharmacological disruption of the actin cytoskeleton. Our results suggest the presence of a novel mechanism involving negative regulation of TRPC channels by calcium entering through the channels. Under physiological conditions, this negative feedback by calcium is attenuated by the presence of closely associated SERCA pumps.