Mechanosensitive Signaling in Gastrointestinal Interstitial Cells of Cajal and Its Role in Motor Function

Gastrointestinal filling and contraction expose the gut wall to changing mechanical loads. Interstitial cells of Cajal (ICC) respond to these loads, but the channels that couple force to pacemaker activity remain incompletely defined. This narrative review examines direct recordings from ICC, proposed channel mechanisms and the epithelial, neural and muscular pathways that shape the motor response. Perfusion shear enhances NaV1.5 current in human jejunal ICC, whereas hypotonic swelling activates a Cl⁻ current in cultured murine ICC whose molecular identity remains unresolved. ANO1 converts intracellular Ca²⁺ signals into depolarization; evidence for its direct mechanical gating is lacking. Piezo1 and TRPM7 are candidate upstream mechanisms in ICC. Piezo2 instead has established functions in epithelial mechanosensing and extrinsic sensory pathways, with effects that depend on the cells and circuits involved. Within the electrically coupled smooth muscle–ICC–PDGFRα⁺ cell network, these inputs alter excitability, propagation and the timing of contraction. Increased local slow-wave frequency can therefore disrupt coordination rather than improve propulsion. Human genetics and tissue studies link channel dysfunction and ICC abnormalities to gastrointestinal motor disorders, but do not yet establish an ICC-specific mechanosensory lesion. Progress toward treatment will require experiments that connect defined mechanical stimuli, currents in identified cells and organ-level motor function.