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The mechanosensor Transient Receptor Potential Vanilloid Member 4 (TRPV4) regulates mouse cholangiocyte secretion and bile formation.
Mechanosensitive signaling has emerged as a mechanism for the regulation of cholangiocyte transport and bile formation. The mechanical effect of fluid-flow, or shear, at the apical membrane of cholangiocytes regulates secretion through a process involving increases in [Ca2+]i and activation of Ca2+-activated Cl- channels. However, the initiating steps translating shear force to increases in [Ca2+]i are unknown. Transient Receptor Potential Vanilloid Member 4 (TRPV4), a non-selective cation channel present in the apical membrane of cholangiocytes, has been proposed as a potential mechanosensor. The aim of the current studies was to determine the potential role of TRPV4 in initiating mechanosensitive signaling in response to fluid-flow in cholangiocytes. TRPV4 expression was confirmed in both small and large mouse cholangiocytes. Exposure of cells to either fluid-flow or specific TRPV4 pharmacologic agonists rapidly increased both [Ca2+]i and membrane cation currents. Both flow- and agonist-stimulated currents displayed identical biophysical properties and were inhibited in the presence of TRPV4 antagonists or in cells after transfection with TRPV4 siRNA. Transfection of mouse cholangiocytes with a TRPV4-EGFP construct increased the expression of TRPV4 and the magnitude of flow-stimulated currents. Lastly, intravenous administration of a specific TRPV4 agonist significantly increased bile flow in mice. The findings are consistent with a model in which activation of cholangiocyte TRPV4 translates shear force to an acute rise in membrane cation permeability, [Ca2+]i, and bile flow. Understanding the role of mechanosensitive transport pathways may provide novel insights to modulate bile flow for the treatment of cholestatic liver disorders.
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