Ca²⁺ Signaling Is the Basis for Pacemaker Activity and Neurotransduction in Interstitial Cells of the GI Tract

Years ago gastrointestinal motility was thought to be due to interactions between enteric nerves and smooth muscle cells (SMCs) in the tunica muscularis. Thus, regulatory mechanisms controlling motility were either myogenic or neurogenic. Now we know that populations of interstitial cells, c-Kit⁺ (interstitial cells of Cajal or ICC), and PDGFRα⁺ cells (formerly "fibroblast-like" cells) are electrically coupled to SMCs, forming the SIP syncytium. Pacemaker and neurotransduction functions are provided by interstitial cells through Ca²⁺ release from the endoplasmic reticulum (ER) and activation of Ca²⁺-activated ion channels in the plasma membrane (PM). ICC express Ca²⁺-activated Cl^- channels encoded by Ano1. When activated, Ano1 channels produce inward current and, therefore, depolarizing or excitatory effects in the SIP syncytium. PDGFRα⁺ cells express Ca²⁺-activated K⁺ channels encoded by Kcnn3. These channels generate outward current when activated and hyperpolarizing or membrane-stabilizing effects in the SIP syncytium. Inputs from enteric and sympathetic neurons regulate Ca²⁺ transients in ICC and PDGFRα⁺ cells, and currents activated in these cells conduct to SMCs and regulate contractile behaviors. ICC also serve as pacemakers, generating slow waves that are the electrophysiological basis for gastric peristalsis and intestinal segmentation. Pacemaker types of ICC express voltage-dependent Ca²⁺ conductances that organize Ca²⁺ transients, and therefore Ano1 channel openings, into clusters that define the amplitude and duration of slow waves. Ca²⁺ handling mechanisms are at the heart of interstitial cell function, yet little is known about what happens to Ca²⁺ dynamics in these cells in GI motility disorders.