Interstitial Cells of Cajal as Pacemakers in the Gastrointestinal Tract

Abstract

▪ Abstract In the gastrointestinal tract, phasic contractions are caused by electrical activity termed slow waves. Slow waves are generated and actively propagated by interstitial cells of Cajal (ICC). The initiation of pacemaker activity in the ICC is caused by release of Ca2+ from inositol 1,4,5-trisphosphate (IP3) receptor–operated stores, uptake of Ca2+ into mitochondria, and the development of unitary currents. Summation of unitary currents causes depolarization and activation of a dihydropyridine-resistant Ca2+ conductance that entrains pacemaker activity in a network of ICC, resulting in the active propagation of slow waves. Slow wave frequency is regulated by a variety of physiological agonists and conditions, and shifts in pacemaker dominance can occur in response to both neural and nonneural inputs. Loss of ICC in many human motility disorders suggests exciting new hypotheses for the etiology of these disorders.

Activation of Ca2+‐activated Cl− channel ANO1 by localized Ca2+ signals

“…Release of Ca 2+ from the IP 3 ‐operated ER stores is the fundamental cellular event that initiates pacemaker activity of ICCs (Sanders et al . 2006). ICCs are electrically coupled to the smooth muscle cells via gap junctions and, thus, rhythmic depolarizations of ICCs are transferred electrically to smooth muscle cells triggering contractions.…”

Enteric ganglioneuritis and abnormal interstitial cells of Cajal

“…Gastrointestinal motility and function require coordination between the intrinsic and extrinsic nervous systems, the interstitial cells of Cajal (ICCs), and smooth muscle cells, where the ICCs are mainly responsible for generation of the pacemaker activity regulating slow waves (1,2).…”

Kit‐like immunoreactivity in the zebrafish gastrointestinal tract reveals putative ICC

“…ICC generate a pacing signal that drives smooth muscle, mediates neuronal input to smooth muscle, and establishes a smooth muscle membrane potential gradient across the thickness of the circular smooth muscle layer (Huizinga et al, 1995;Farrugia et al, 2003;Strege et al, 2003;Ward et al, 2004;Sanders et al, 2006). Disturbances in ICC distribution have been correlated with GI dysmotilities in animal model systems, and in humans (He et al, 2000(He et al, , 2001Huizinga et al, 2001;Lyford et al, 2002;Sanders et al, 2006). The zebrafish is a well-established model system for studies on development, and is an important model system for human disease (Dodd et al, 2000;Goldsmith, 2004).…”