Interstitial cells of Cajal - pacemakers of the gastrointestinal tract

Gastrointestinal (GI) organs display spontaneous, non-neurogenic electrical, and mechanical rhythmicity that underlies fundamental motility patterns, such as peristalsis and segmentation. Electrical rhythmicity (aka slow waves) results from pacemaker activity generated by interstitial cells of Cajal (ICC). ICC express a unique set of ionic conductances and Ca²⁺ handling mechanisms that generate and actively propagate slow waves. GI smooth muscle cells lack these conductances. Slow waves propagate actively within ICC networks and conduct electrotonically to smooth muscle cells via gap junctions. Slow waves depolarize smooth muscle cells and activate voltage-dependent Ca²⁺ channels (predominantly CaV1.2), causing Ca²⁺ influx and excitation-contraction coupling. The main conductances responsible for pacemaker activity in ICC are ANO1, a Ca²⁺-activated Cl^- conductance, and CaV3.2. The pacemaker cycle, as currently understood, begins with spontaneous, localized Ca²⁺ release events in ICC that activate spontaneous transient inward currents due to activation of ANO1 channels. Depolarization activates Ca_V3.2 channels, causing the upstroke depolarization phase of slow waves. The upstroke is transient and followed by a long-duration plateau phase that can last for several seconds. The plateau phase results from Ca²⁺-induced Ca²⁺ release and a temporal cluster of localized Ca²⁺ transients in ICC that sustains activation of ANO1 channels and clamps membrane potential near the equilibrium potential for Cl^- ions. The plateau phase ends, and repolarization occurs, when Ca²⁺ stores are depleted, Ca²⁺ release ceases and ANO1 channels deactivate. This review summarizes key mechanisms responsible for electrical rhythmicity in gastrointestinal organs.