Role of muscarinic receptor anatgonist in primary cilia structure

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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.