Piezo1, the pancreas' predominant mechano-gated ion channel, is highly expressed in pancreatic acinar cells. Despite specific advances in understanding the pathological effects of Piezo1 in pancreatitis and fibrosis, the physiological function of Piezo1 in the exocrine pancreas is unknown. We observed that the physiological concentration of the secretagogue cholecystokinin (CCK) triggers dynamic changes in cell volume in pancreatic acini, causing a rapid, transient increase in cell volume followed by cell contraction, raising the possibility that plasma membrane deformation can open mechano-gated calcium channels, including Piezo1. As a calcium permeable cation channel, we proposed that Piezo1 may regulate pancreatic secretion. To test this hypothesis, we found that the Piezo1 agonist, Yoda1 (2 µm), produced wave-like [Ca²⁺]_i oscillations and the formation of F-actin-coated exocytotic granules at the apical acinar cell membrane similar to normal secretagogue-stimulated exocrine secretion. Consistent with these observations, Yoda1 stimulated amylase release in acini from wild-type mice but not mice with selective deletion of Piezo1 in acinar cells (Piezo1^aci KO). These findings indicate that Piezo1 activation is sufficient to stimulate acinar cell exocytosis. To determine the role of Piezo1 in secretagogue-stimulated exocytosis, we found that CCK-stimulated [Ca²⁺]_i oscillations and amylase release were substantially inhibited in Piezo1^aci KO acinar cells. Importantly, low dose Yoda1 (500 nM) shifted the CCK-mediated amylase secretion dose-response curve ten-fold to the left, indicating that Piezo1 activation significantly increased acinar cell sensitivity to CCK. Thus, secretagogue-mediated dynamic changes in cell volume activate Piezo1, which is necessary to maintain sustained wave-like [Ca²⁺]_i oscillations that facilitate exocytosis. We demonstrate that secretagogue-stimulated exocytosis is accompanied by dynamic changes in acinar cell volume that activate Piezo1 channels, which may both trigger and facilitate exocytosis. These studies unveil a previously unrecognized physiological mechanosensing function regulating exocytosis. We postulate that Piezo1 can be a regulator of pancreatic secretion and a target for pancreatic insufficiency.

Rodger Liddle

Duke University Medical Center

Appearances