Dopamine receptor type 5 in the primary cilia has dual chemo- and mechano-sensory roles.
Dopamine receptor type 5 in the primary cilia has dual chemo- and mechano-sensory roles.
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DOI：
10.1161/hypertensionaha.111.172080
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发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Nauli SM
中科院分区：
文献类型：
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作者：
Abdul-Majeed S;Nauli SM
多囊肾病（PKD）的特点是心血管异常，包括高血压。多巴胺是一种循环激素，与人类和动物模型中的原发性高血压有关。已知血管内皮初级纤毛具有机械感觉细胞器的功能。尽管初级纤毛和多巴胺受体在血管性高血压中都发挥着重要作用，但它们的关系从未被探索过。为了确定多巴胺能系统和机械感觉纤毛的作用，我们研究了多巴胺对野生型（WT）和机械不敏感多囊突变细胞（Pkd1−/− 和 Tg737orpk/orpk）中纤毛长度和功能的影响。我们首次发现小鼠血管内皮细胞具有 5 型多巴胺受体 (DR5)，该受体在培养细胞和体内小鼠动脉中共定位于初级纤毛。 DR5 激活通过丝切蛋白和肌动蛋白聚合增加动脉和内皮细胞中的纤毛长度。 DR5 激活还可恢复突变细胞中的纤毛功能。此外，沉默 DR5 会完全消除 WT 细胞中的机械纤毛功能。我们发现 DR5 在纤毛长度和功能中起着非常重要的作用。此外，纤毛的化学感觉功能可以通过改变对流体剪切应力的敏感性来改变机械感觉功能。我们认为激活的纤毛 DR5 在内皮细胞中具有功能性机械感觉作用。
Polycystic kidney disease (PKD) is characterized by cardiovascular irregularities, including hypertension. Dopamine, a circulating hormone, is implicated in essential hypertension in humans and animal models. Vascular endothelial primary cilia are known to function as mechano-sensory organelles. Though both primary cilia and dopamine receptors play important roles in vascular hypertension, their relationship has never been explored. To determine the roles of the dopaminergic system and mechanosensory cilia, we studied the effects of dopamine on ciliary length and function in wild-type (WT) and mechano-insensitive polycystic mutant cells (Pkd1−/− and Tg737orpk/orpk). We show for the first time that mouse vascular endothelia exhibit dopamine receptor-type 5 (DR5), which co-localizes to primary cilia in cultured cells and mouse arteries in vivo. DR5 activation increases cilia length in arteries and endothelial cells through cofilin and actin polymerization. DR5-activation also restores cilia function in the mutant cells. In addition, silencing DR5 completely abolishes mechano-ciliary function in WT cells. We find that DR5 plays very important roles in ciliary length and function. Furthermore, the chemosensory function of cilia can alter the mechanosensory function through changes in sensitivity to fluid-shear stress. We propose that activated ciliary DR5 has a functional mechanosensory role in endothelial cells.