Increased vascular smooth muscle contractility in TRPC6-/- mice
Increased vascular smooth muscle contractility in TRPC6-/- mice
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DOI：
10.1128/mcb.25.16.6980-6989.2005
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发表时间：
2005-08-01
影响因子：
5.3
通讯作者：
Birnbaumer, L
中科院分区：
文献类型：
--
作者：
Dietrich, A;Schnitzler, MMY;Birnbaumer, L
在TRPC(经典瞬时受体电位)通道亚家族中，TRPC3、-6和-7被激活C型磷脂酶的信号转导通路以及直接暴露于二酰甘油所调控。由于TRPC6在肺和血管平滑肌细胞中高表达，它可能是受体操作阳离子进入的候选分子。为了确定TRPC6的生理作用，我们建立了TRPC6缺陷小鼠模型。这些小鼠表现出血压升高，激动剂诱导的离体主动脉环和脑动脉收缩能力增强。TRPC6基因缺陷小鼠的平滑肌细胞具有更高的基础阳离子进入，更多的携带TRPC的阳离子电流，以及更多的去极化的膜电位。然而，这种更高的基础阳离子进入被原代TPPC6(-/-)平滑肌细胞中TRPC3特异性小干扰RNA的表达完全取消。沿着这些路线，TRPC3在野生型细胞中的表达导致基础活性增加，而TRPC6(-/-)平滑肌细胞中TRPC6的表达导致基础阳离子内流减少。这些发现表明，在缺乏TRPC6的平滑肌细胞中上调的结构性活性TRPC3型通道不能在功能上取代TRPC6。因此，TRPC6在控制血管平滑肌张力方面具有明显的非多余作用。
Among the TRPC subfamily of TRP (classical transient receptor potential) channels, TRPC3, -6, and -7 are gated by signal transduction pathways that activate C-type phospholipases as well as by direct exposure to diacylglycerols. Since TRPC6 is highly expressed in pulmonary and vascular smooth muscle cells, it represents a likely molecular candidate for receptor-operated cation entry. To define the physiological role of TR-PC6, we have developed a TRPC6-deficient mouse model. These mice showed an elevated blood pressure and enhanced agonist-induced contractility of isolated aortic rings as well as cerebral arteries. Smooth muscle cells of TRPC6-deficient mice have higher basal cation entry, increased TRPC-carried cation currents, and more depolarized membrane potentials. This higher basal cation entry, however, was completely abolished by the expression of a TRPC3-specific small interference RNA in primary TPPC6(-/-) smooth muscle cells. Along these lines, the expression of TRPC3 in wild-type cells resulted in increased basal activity, while TRPC6 expression in TRPC6(-/-) smooth muscle cells reduced basal cation influx. These findings imply that constitutively active TRPC3-type channels, which are up-regulated in TRPC6-deficient smooth muscle cells, are not able to functionally replace TRPC6. Thus, TRPC6 has distinct nonredundant roles in the control of vascular smooth muscle tone.