Differences in TRPC3 and TRPC6 channels assembly in mesenteric vascular smooth muscle cells in essential hypertension
Differences in TRPC3 and TRPC6 channels assembly in mesenteric vascular smooth muscle cells in essential hypertension
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DOI：
10.1113/jp273327
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发表时间：
2017-03-01
影响因子：
5.5
通讯作者：
Ramon Lopez-Lopez, Jose
中科院分区：
文献类型：
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作者：
Alvarez-Miguel, Ines;Cidad, Pilar;Ramon Lopez-Lopez, Jose
原发性高血压患者血管张力增高涉及总外周阻力的持续升高。已经提出了一个模型，其中膜去极化和更高的l型Ca2+通道活性的结合产生增强的Ca2+内流到血管平滑肌细胞（VSMCs），收缩和血管收缩。对负责膜去极化的罪魁祸首离子通道的研究已经提供了几种候选离子通道，包括典型瞬时受体电位（TRPC）家族的成员。TRPC3和TRPC6是二酰基甘油激活的非选择性阳离子通道，有助于拉伸或激动剂诱导的去极化。关于高血压患者TRPC3/TRPC6功能表达的变化存在矛盾的信息。然而，尽管TRPC3-TRPC6通道可以异质多分子化，但其关联模式的差异可能会改变其对血管张力的功能贡献，这种可能性在很大程度上尚未被探索。我们利用原发性高血压（BPH小鼠，血压高）模型及其正常控制（BPN小鼠，血压正常）来验证这一假设。首先，从转染的中国仓鼠卵巢细胞中记录的同源和异源四聚体的非选择性阳离子电流表明，TRPC电流仅在TRPC6存在时才对选择性拮抗剂Pyr10敏感，而细胞内抗trpc3抗体选择性阻断trpc3介导的电流。在肠系膜VSMCs中，BPN细胞中基底电流和激动剂诱导电流对Pyr3和Pyr10更为敏感。肌图研究一致显示，BPN肠系膜动脉中pyr3 /10诱导的血管扩张更大。mRNA和蛋白表达数据支持TRPC3和TRPC6比例和组装的变化，BPH vsmcs中较高的TRPC3通道贡献可能有利于细胞去极化。这些TRPC3和TRPC6通道的功能和药理特性的差异，取决于它们的组装，可能代表着新的治疗机会。
Increased vascular tone in essential hypertension involves a sustained rise in total peripheral resistance. A model has been proposed in which the combination of membrane depolarization and higher L-type Ca2+ channel activity generates augmented Ca2+ influx into vascular smooth muscle cells (VSMCs), contraction and vasoconstriction. The search for culprit ion channels responsible for membrane depolarization has provided several candidates, including members of the canonical transient receptor potential (TRPC) family. TRPC3 and TRPC6 are diacylglycerol-activated, non-selective cationic channels contributing to stretch-or agonist-induced depolarization. Conflicting information exists regarding changes in TRPC3/TRPC6 functional expression in hypertension. However, although TRPC3-TRPC6 channels can heteromultimerize, the possibility that differences in their association pattern may change their functional contribution to vascular tone is largely unexplored. We probe this hypothesis using a model of essential hypertension (BPH mice; blood pressure high) and its normotensive control (BPN mice; blood pressure normal). First, non-selective cationic currents through homo-and heterotetramers recorded from transfected Chinese hamster ovary cells indicated that TRPC currents were sensitive to the selective antagonist Pyr10 only when TRPC6 was present, whereas intracellular anti-TRPC3 antibody selectively blocked TRPC3-mediated currents. In mesenteric VSMCs, basal and agonist-induced currents were more sensitive to Pyr3 and Pyr10 in BPN cells. Consistently, myography studies showed a larger Pyr3/10-induced vasodilatation in BPN mesenteric arteries. mRNA and protein expression data supported changes in TRPC3 and TRPC6 proportions and assembly, with a higher TRPC3 channel contribution in BPH VSMCsthat could favour cell depolarization. These differences in functional and pharmacological properties of TRPC3 and TRPC6 channels, depending on their assembly, could represent novel therapeutical opportunities.