Differential PI 3-kinase dependence of early and late phases of recycling of the internalized AT1 angiotensin receptor.
Differential PI 3-kinase dependence of early and late phases of recycling of the internalized AT1 angiotensin receptor.
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DOI：
10.1083/jcb.200111013
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发表时间：
2002-06-24
期刊：
影响因子：
--
通讯作者：
Balla T
中科院分区：
文献类型：
--
作者：
Hunyady L;Baukal AJ;Gaborik Z;Olivares-Reyes JA;Bor M;Szaszak M;Lodge R;Catt KJ;Balla T
在表达绿色荧光蛋白(GFP)或血凝素标记的AT1受体(AT1R)的HEK 293细胞中，研究了激动剂诱导的AT1血管紧张素受体(AT1R)的内吞和加工。经Ang II刺激后，受体及其配体与Rab5-GFP和Rab4-GFP共同定位于早期的内吞体内，随后与Rab11-GFP共同定位于中央周围循环的内体。Wortmannin(WT)或LY294002对磷脂酰肌醇(PI)3-激酶的抑制可导致形成异质Rab组分的大的内体小泡，在其极限膜和小的相关囊泡结构中含有配体-受体复合体。与Alexa®-转铁蛋白不同，Alexa®-转铁蛋白主要存在于WT处理细胞中与大小泡外部相关的小小泡中，而罗丹明-Ang II也被分离到小的内部小泡中。在标记有125I-Ang II的细胞中，WT处理不影响受体内吞速率，但显著减少受体循环的初始阶段，而不影响其缓慢成分。同样，WT抑制Ang II刺激终止后AT1R在细胞表面恢复的早期成分，而不是缓慢成分。这些数据表明，内化的AT1受体是通过类似于多囊泡体的小泡处理的，并通过依赖PI 3-激酶的快速循环途径以及对PI 3-激酶抑制剂不太敏感的较慢途径循环到细胞表面。
Agonist-induced endocytosis and processing of the G protein–coupled AT1 angiotensin II (Ang II) receptor (AT1R) was studied in HEK 293 cells expressing green fluorescent protein (GFP)– or hemagglutinin epitope–tagged forms of the receptor. After stimulation with Ang II, the receptor and its ligand colocalized with Rab5–GFP and Rab4–GFP in early endosomes, and subsequently with Rab11–GFP in pericentriolar recycling endosomes. Inhibition of phosphatidylinositol (PI) 3-kinase by wortmannin (WT) or LY294002 caused the formation of large endosomal vesicles of heterogeneous Rab composition, containing the ligand–receptor complex in their limiting membranes and in small associated vesicular structures. In contrast to Alexa®–transferrin, which was mainly found in small vesicles associated with the outside of large vesicles in WT-treated cells, rhodamine–Ang II was also segregated into small internal vesicles. In cells labeled with 125I-Ang II, WT treatment did not impair the rate of receptor endocytosis, but significantly reduced the initial phase of receptor recycling without affecting its slow component. Similarly, WT inhibited the early, but not the slow, component of the recovery of AT1R at the cell surface after termination of Ang II stimulation. These data indicate that internalized AT1 receptors are processed via vesicles that resemble multivesicular bodies, and recycle to the cell surface by a rapid PI 3-kinase–dependent recycling route, as well as by a slower pathway that is less sensitive to PI 3-kinase inhibitors.
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