David Beech PIEZO1 force sensing ion channel

>> YOUR LINK HERE: ___ http://youtube.com/watch?v=2CGvsmLhCBA

PIEZO1 forms calcium-permeable non-selective cation channels that are sensitive to activation by mechanical forces. Emerging concepts for the channels and potential new research directions will be discussed. We identified importance of PIEZO1 in cardiovascular biology, showing its sensitivity to the physiological force of fluid shear stress and roles in embryonic vascular maturation, elevated blood pressure of whole body physical activity, capillary density in skeletal muscle and physical exercise performance. We found that endothelial cells disable intrinsic inactivation in the channels via SMPD3 catalytic activity and ceramide, enabling sustained functions. We developed molecular dynamics simulations of the channels in endothelial membranes to begin to understand how the channels work at the molecular level and interact with lipids. We identified downstream signalling to calpain, nitric oxide production via NOS3, NOTCH1 via ADAM10, cell apoptosis via NOS3 and its signalling to pericyte thrombospondin-2, and integration with cell adhesion molecules PECAM1 and CADH5 for force dependent remodelling of cell junctions. We found functions also in cardiac fibroblasts where the channels regulate inflammation and fibrosis via p38, interleukin-6 and tenascin c. Through medicinal chemistry studies of the Yoda1 small-molecule, we found new modulators with different properties and improved efficacy, potency and solubility. In studies with human genetics collaborators, we identified missense mutations associated with Generalised Lymphatic Dysplasia that disrupt channel function, showing partial normalisation of such channels by novel PIEZO1 agonists. Collaboration with Nanion enabled automated 384-well “mechano-patch-clamp” for quantifying PIEZO1 activities and sensitivities to small-molecule agonists and antagonists. PIEZO1 importance is thus emerging and opportunities are arising for new pharmacology with potential therapeutic value. • _____________________________________________________________________ • Discover our Product Portfolio, visit: https://www.nanion.de/products/ • More details about the User Meeting: https://www.nanion.de/nanion-user-mee... • Stay up-to-date with upcoming events: https://www.nanion.de/news/

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