Recent Advances in the Study of Cellular Mechanisms of the Generation of Spontaneous Activity in Gastric Muscle

Gastric smooth muscles are spontaneously active with generation of slow waves and action potentials, and these activities have been considered myogenic in origin. However, it has been one of the mysterious events that single cell preparations of the stomach do not produce spontaneous activity. Histological observations pointed out that interstitial cells found by Cajal (Interstitial cells of Cajal, ICC) might be pacemaker cells of intestinal movements, since ICC are rich in mitochondria and have gap junctional connections with smooth muscle cells. In mice, mutation of c-kit gene was found associated with disorder of gastrointestinal movements, and these mice were absent from ICC. These observations opened a new world for the study of pacemaker mechanisms in gastrointestinal smooth muscle, and many electrophysiological, immunohistochemical, genetic and biochemical studies indicated that ICC were indeed the pacemakers for gastrointestinal activity. ICC distributed widely in the gastrointestinal wall, and were classified into several groups. A group of ICC distributed in the myenteric layer (ICC-MY) was working as a pacemaker of gastrointestinal smooth muscle. Pacemaker potentials with fast rising and following plateau components were generated in ICC-MY, and the potentials were conducted to circular smooth muscles to trigger slow waves and also conducted passively to longitudinal muscles to form follower potentials. In circular muscle preparations, interstitial cells distributed within muscle bundles (ICC-IM) produced unitary potentials, which were conducted to circular muscles to form slow potentials by summation. In mutant mice lacking inositol trisphosphate (IP3) receptor, slow waves were absent in gastric smooth muscles. The generation of spontaneous activity in stomach muscle was impaired by the inhibition of Ca2+-release from internal stores through IP3 receptors, inhibition of mitochon-drial Ca2+-handling with proton pump inhibitors and inhibition of ATP-sensitive K+ channels at the mitochondrial inner membrane. These results suggested that mitochondrial Ca2+-handling produce spontaneous activities in pacemaker cells. Possible involvement of protein kinase C in the Ca2+ signaling system was also suggested. The recent finding in the causal relationship between impairment of ICC and gastrointestinal disorder has also been briefly introduced.