Abstract
Piezo1, a mechanosensitive Ca2+-permeable non-selective cationic ion channel protein, is involved in a wide range of biological processes and plays crucial roles in vascular development. However, the pharmacology of this protein is in its infancy. Yoda1, the first specific chemical activator of Piezo1 channels, can activate Piezo1 in absence of mechanical stimulation. Hence, we sought to identify inhibitors of Yoda1 from Traditional Chinese Medicine (TCM). Intracellular Ca2+ measurements were conducted in human umbilical vein endothelial cells (HUVECs), HEK 293T cells overexpressing TRPC5 and TRPM2 channels, as well as in CHO K1 cells overexpressing TRPV4 channels. We identified tubeimoside I (TBMS1) as a strong inhibitor of the Yoda1 response and demonstrated its selectivity for the Piezo1 channels. Similarly, Yoda1-induced inhibitory results were obtained in Piezo1 wild-type overexpressed cells, murine liver endothelial cells (MLECs), and macrophages. The physiological responses of TBMS1 were identified by isometric tension, which can inhibit Yoda1 relaxation of aortic rings. Our results demonstrated that TBMS1 can effectively antagonize Yoda1 induced Piezo1 channel activation. This study sheds light on the existence of Yoda1 inhibitors and improves the understanding of vascular pharmacology through Piezo1 channels.
Highlights
Piezo1 is a mechanically activated ion channel involved in a wide range of biological functions, including touch perception, proprioception, and vascular blood flow (Wu et al, 2017; Zhao et al, 2018)
tubeimoside I (TBMS1) had a concentration-dependent inhibitory effect on Yoda1-induced Ca2+ entry, with an IC50 of 1.11 mM (Figure 1H). These data support that TBMS1 is an antagonist of Yoda1induced Piezo1 channels in endothelial cells
Given that TBMS1 can inhibit Yoda1 response in human umbilical vein endothelial cells (HUVECs), we explored whether TBMS1 has similar inhibitory effects in native cells
Summary
Piezo is a mechanically activated ion channel involved in a wide range of biological functions, including touch perception, proprioception, and vascular blood flow (Wu et al, 2017; Zhao et al, 2018). Tubeimoside I and Piezo Channel dysplasia, consistent with the protein's importance in regulation of erythrocyte volume and epithelial cell homeostasis (Eisenhoffer et al, 2012; Zarychanski et al, 2012; Albuisson et al, 2013; Fotiou et al, 2015; Lukacs et al, 2015; Andolfo et al, 2016; Gudipaty et al, 2017). These observations demonstrate the functional value of Piezo channels and their feasibility as a medicinal target
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