Caveolin-dependent angiotensin II type 1 receptor signaling in vascular smooth muscle.
Caveolin-dependent angiotensin II type 1 receptor signaling in vascular smooth muscle.
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DOI：
10.1161/01.hyp.0000242907.70697.5d
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发表时间：
2006-11
期刊：
影响因子：
8.3
通讯作者：
M. Ushio-Fukai;R. Alexander
中科院分区：
文献类型：
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作者：
M. Ushio-Fukai;R. Alexander
血管紧张素II（AngII）是血管平滑肌细胞（VSMC）中的多能激素，并刺激动脉肥大，这是高血压重塑的标志。这些作用主要通过G蛋白偶联受体Ang II 1型受体（AT 1 R）介导。1在VSMC中，AT 1 R介导的信号传导是双相的，激动剂/受体复合物内化为我们所说的“信号传导结构域”是信号传导的紧张相所必需的（最初以磷脂酶D激活为特征），但不用于最初的磷脂酶C刺激，2这一证据与空间离散的Ang II信号结构域的存在相一致。我们发现血管紧张素II诱导的磷脂酶激活是通过≥2个Gα亚基介导的，（Gαq和Gα12/13），以及它们相关的Gβγ组分。3，4此外，各种非受体酪氨酸激酶，包括cAbl和一些Src家族，以及促分裂原活化蛋白激酶和Akt，被血管紧张素II激活并介导VSMC肥大和生长。5 -7这些途径的激活部分依赖于酪氨酸磷酸化表皮生长因子受体（EGF-R）的（反式调节），其充当cSrc和Pyk 2组装的“支架”，导致细胞外调节激酶（ERK）1/2和Akt.8的下游活化，9这些结果与需要VSMC中AT 1 R信号库的时间分散和组织的模型一致。7，10越来越多的证据表明，受体及其相关的信号分子并不是随机分布在细胞膜中，而是定位在专门的信号结构域中。在质膜中，已经鉴定出由鞘糖脂和胆固醇在膜双层内的侧向包装形成的功能不同的微区。这些结构域称为“脂筏”，与膜运输和细胞信号传导机制有关，并为...
Angiotensin II (Ang II) is a pluripotent hormone in vascular smooth muscle cells (VSMCs) and stimulates arterial hypertrophy, a hallmark of remodeling in hypertension. These effects are mediated primarily through the G protein–coupled receptor Ang II type 1 receptor (AT1R).1 In VSMCs, AT1R-mediated signaling is biphasic, and internalization of the agonist/receptor complex into what we called a “signaling domain” is required for the tonic phase of signaling (initially characterized by phospholipase D activation) but not for the initial phospholipase C stimulation, which occurs at the cell surface.2 This evidence was consistent with the existence of spatially discrete Ang II signaling domains. We showed that sequential Ang II–induced phospholipase activation is mediated through ≥2 Gα subunits (Gαq and Gα12/13), as well as their associated Gβγ components.3,4 In addition, various nonreceptor tyrosine kinases, including cAbl and some from the Src family, as well as mitogen-activated protein kinases and Akt, are activated by Ang II and mediate VSMC hypertrophy and growth.5–7 Activation of these pathways is in part dependent on tyrosine phosphorylation (transmodulation) of the epidermal growth factor receptor (EGF-R), which serves as a “scaffold” for the assembly of cSrc and Pyk2, leading to downstream activation of extracellular-regulated kinase (ERK)1/2 and Akt.8,9 These results are consistent with a model that requires temporal dispersion and organization of the AT1R signaling repertoire in VSMCs.7,10 Accumulating evidence suggests that receptors and the signaling molecules with which they associate are not randomly distributed in the cell membrane but are localized in specialized signaling domains. Functionally distinct microdomains, formed by the lateral packing of glycosphingolipids and cholesterol within the membrane bilayer, have been identified in plasma membranes. These domains, called “lipid rafts,” have been implicated in membrane trafficking and cellular signaling mechanisms and serve …