Mechanosensing Piezo channels in gastrointestinal disorders

Abstract

All cells in the body are exposed to physical force in the form of tension, compression, gravity, shear stress, or pressure. Cells convert these mechanical cues into intracellular biochemical signals; this process is an inherent property of all cells and is essential for numerous cellular functions. A cell's ability to respond to force largely depends on the array of mechanical ion channels expressed on the cell surface. Altered mechanosensing impairs conscious senses, such as touch and hearing, and unconscious senses, like blood pressure regulation and gastrointestinal (GI) activity. The GI tract's ability to sense pressure changes and mechanical force is essential for regulating motility, but it also underlies pain originating in the GI tract. Recent identification of the mechanically activated ion channels Piezo1 and Piezo2 in the gut and the effects of abnormal ion channel regulation on cellular function indicate that these channels may play a pathogenic role in disease. Here, we discuss our current understanding of mechanically activated Piezo channels in the pathogenesis of pancreatic and GI diseases, including pancreatitis, diabetes mellitus, irritable bowel syndrome, GI tumors, and inflammatory bowel disease. We also describe how Piezo channels could be important targets for treating GI diseases.

Figure 1. Model of mechanosensing in the pancreas.

(A) Piezo1-induced TRPV4 opening causes intracellular calcium ([Ca²⁺]_i) elevation in acinar cells and is responsible for pressure-induced pancreatitis. Pressure or shear stress force opens Piezo1 channels, which induces phospholipase A₂ (PLA₂) and activates TRPV4. Sustained elevation in [Ca²⁺]_i leads to mitochondrial depolarization, lysosome–zymogen granule fusion, trypsinogen activation, and pancreatitis. (B) Piezo1-induced [Ca²⁺]_i elevation through glucose-triggered dynamic changes in volume and deformation in cell membrane facilitates insulin release from pancreatic β cells. (C) Pressure-sensing Piezo1 channel signaling activates PSCs. The activated phenotype lacks perinuclear fat droplets and shows increased levels of TGF-β1, fibronectin, and type I collagen that contribute to pancreatic fibrosis. VGCC, voltage-gated calcium channel.

Figure 2. Schematic depiction of mechanosensing functions of Piezo1 and Piezo2 in the gut.

Piezo1 is expressed on stem cells of the intestinal crypt, enteroendocrine cells (EECs), and goblet cells and stimulates stem cell proliferation, EEC differentiation, and mucus production, respectively. Piezo2 in enterochromaffin cells triggers 5-HT release and mediates visceral hypersensitivity.