Merely touching the pancreas can lead to premature zymogen activation and pancreatitis but the mechanism is not completely understood. Here we demonstrate that pancreatic acinar cells express the mechanoreceptor Piezo1 and application of pressure within the gland produces pancreatitis. To determine if this effect is through Piezo1 activation, we induce pancreatitis by intrapancreatic duct instillation of the Piezo1 agonist Yoda1. Pancreatitis induced by pressure within the gland is prevented by a Piezo1 antagonist. In pancreatic acinar cells, Yoda1 stimulates calcium influx and induces calcium-dependent pancreatic injury. Finally, selective acinar cell-specific genetic deletion of Piezo1 protects mice against pressure-induced pancreatitis. Thus, activation of Piezo1 in pancreatic acinar cells is a mechanism for pancreatitis and may explain why pancreatitis develops following pressure on the gland as in abdominal trauma, pancreatic duct obstruction, pancreatography, or pancreatic surgery. Piezo1 blockade may prevent pancreatitis when manipulation of the gland is anticipated.

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tion of biliary secretion through apical purinergic receptors in cultured rat cholangiocytes. Am. J. Physiol. 273 (Gastrointest. Liver Physiol. 36): G1108-G1117, 1997.-To evaluate whether ATP in bile serves as a signaling factor regulating ductular secretion, voltage-clamp studies were performed using a novel normal rat cholangiocyte (NRC) model. In the presence of amiloride (100 µM) to block Na ϩ channels, exposure of the apical membrane to ATP significantly increased the shortcircuit current (I sc ) from 18.2 Ϯ 5.9 to 52.8 Ϯ 12.7 µA (n ϭ 18). The response to ATP is mediated by basolateral-to-apical Cl Ϫ transport because it is inhibited by 1) the Cl Ϫ channel blockers 4,4Ј-diisothiocyanostilbene-2,2Ј-disulfonic acid (1 mM), diphenylanthranilic acid (1.5 mM), or 5-nitro-2-(3-phenylpropylamino)benzoic acid (50 or 100 µM) in the apical chamber, 2) the K ϩ channel blocker Ba 2ϩ (5 mM), or 3) the Na ϩ -K ϩ -2Cl Ϫ cotransport inhibitor bumetanide (200 µM) in the basolateral chamber. Other nucleotides stimulated an increase in I sc with a rank order potency of UTP ϭ ATP ϭ adenosine 5Ј-O-(3)-thiotriphosphate, consistent with P 2u purinergic receptors. ADP, AMP, 2-methylthioadenosine 5Ј-triphosphate, and adenosine had no effect. A cDNA encoding a rat P 2u receptor (rP 2u R) was isolated from a liver cDNA library, and functional expression of the corresponding mRNA in Xenopus laevis oocytes resulted in the appearance of ATP-stimulated currents with a similar pharmacological profile. Northern analysis identified hybridizing mRNA transcripts in NRC as well as other cell types in rat liver. These findings indicate that exposure of polarized cholangiocytes to ATP results in luminal Cl Ϫ secretion through activation of P 2u receptors in the apical membrane. Release of ATP into bile may serve as an autocrine or paracrine signal regulating cholangiocyte secretory function.