Ca²⁺ dynamics in interstitial cells: foundational mechanisms for the motor patterns in the gastrointestinal tract

The gastrointestinal (GI) tract displays multiple motor patterns that move nutrients and wastes through the body. Smooth muscle cells (SMCs) provide the forces necessary for GI motility, but interstitial cells, electrically coupled to SMCs, tune SMC excitability, transduce inputs from enteric motor neurons, and generate pacemaker activity that underlies major motor patterns, such as peristalsis and segmentation. The interstitial cells regulating SMCs are interstitial cells of Cajal (ICC) and PDGF receptor (PDGFR)α⁺ cells. Together these cells form the SIP syncytium. ICC and PDGFRα⁺ cells express signature Ca²⁺-dependent conductances: ICC express Ca²⁺-activated Cl^- channels, encoded by Ano1, that generate inward current, and PDGFRα⁺ cells express Ca²⁺-activated K⁺ channels, encoded by Kcnn3, that generate outward current. The open probabilities of interstitial cell conductances are controlled by Ca²⁺ release from the endoplasmic reticulum. The resulting Ca²⁺ transients occur spontaneously in a stochastic manner. Ca²⁺ transients in ICC induce spontaneous transient inward currents and spontaneous transient depolarizations (STDs). Neurotransmission increases or decreases Ca²⁺ transients, and the resulting depolarizing or hyperpolarizing responses conduct to other cells in the SIP syncytium. In pacemaker ICC, STDs activate voltage-dependent Ca²⁺ influx, which initiates a cluster of Ca²⁺ transients and sustains activation of ANO1 channels and depolarization during slow waves. Regulation of GI motility has traditionally been described as neurogenic and myogenic. Recent advances in understanding Ca²⁺ handling mechanisms in interstitial cells and how these mechanisms influence motor patterns of the GI tract suggest that the term "myogenic" should be replaced by the term "SIPgenic," as this review discusses.