Role of muscarinic receptor anatgonist in primary cilia structure

摘要： 初级内皮纤毛是机械感觉细胞器，投射到血管的管腔和 肾小管。纤毛组装或功能缺陷可导致多种人类病理，包括 高血压和多囊肾病(PKD)。乙酰胆碱是一种神经递质，与 人类的高血压。已经证明，血管内皮细胞需要初级纤毛来感觉和 将外部机械刺激转化为内部生化反应。这些反应之一包括 生物合成和释放一氧化氮，这是最有效的内源性血管扩张剂之一。虽然两者都是 初级纤毛和M胆碱受体在高血压中起重要作用，它们之间的关系有 从未被探索过。为了确定胆碱能系统和机械感觉纤毛的作用，我们研究了 乙酰胆碱受体调节剂对野生型和机械型纤毛长度和功能的影响 纤毛不敏感突变内皮细胞(PKD1orpk和Tg737orpk/−/−)。我们实验室的研究首次表明 小鼠血管内皮细胞呈现M受体-1、3和5型(AChM1、3和5R)，它们共同促进血管内皮细胞的生长。 定位于初级内皮纤毛。AChM3R激活可显著增加细胞纤毛长度 AChM3R激动剂与未处理细胞的比较。此外，纤毛的化学感觉功能可以改变 通过改变对流体剪应力的敏感度来实现机械传感功能。我们建议激活的睫状体 AChM3R对血管内皮细胞具有功能性的机械感觉作用。我们在目前的研究中提出 AChM3R拮抗剂会产生相反的作用，缩短纤毛长度。这也会削弱纤毛的感觉。 在没有生产的情况下运行。

Abstract: Primary endothelial cilia are mechanosensory organelles that are projected into the lumen of blood vessels and kidney tubules. Defects in cilia assembly or function can lead to multiple human pathologies, including hypertension and Polycystic Kidney Disease (PKD). Acetylcholine, a neurotransmitter, is implicated in essential hypertension in humans. It has been demonstrated that vascular endothelia require primary cilia to sense and transmit external mechanical stimuli into internal biochemical reactions. One of these reactions includes the biosynthesis and release of nitric oxide, which is one of the most potent endogenous vasodilators. Though both primary cilia and muscarinic acetylcholine receptors play important roles in hypertension, their relationship has never been explored. To determine the roles of the cholinergic system and mechanosensory cilia, we studied the effects of acetylcholine receptor modulators on ciliary length and function in wild-type (WT) and mechano- insensitive cilia mutant endothelial cells (Pkd1−/− and Tg737orpk/orpk). Studies from our lab showed for the first time that mouse vascular endothelia exhibit muscarinic receptor-type 1, 3 and 5 (AChM1, 3, and 5R), which co- localizes to primary endothelial cilia. AChM3R activation significantly increases cilia length in cells treated with AChM3R agonist compared to non-treated cells. Furthermore, the chemosensory function of cilia can alter the mechanosensory function through changes in sensitivity to fluid-shear stress. We propose that activated ciliary AChM3R has a functional mechanosensory role in endothelial cells. We propose in the current study that AChM3R antagonist will have the opposite effect and shorten cilia length. This could also diminish cilia sensory function in response to NO production.