Involvement of interstitial cells of Cajal in the control of smooth muscle excitability

Abstract

Many tissues which contain smooth muscles generate spontaneous electrical and mechanical activity, which persists in the absence of stimulation. In some tissues, activity is triggered by stretch and usually results from membrane depolarization caused by activation of stretch-dependent channels in the membranes of individual smooth muscle cells, with the depolarization-activating membrane potential dependent ion-selective channels. In other tissues, the smooth muscle cells, the ‘resting’ membrane potential is depolarized, so leading to the activation of voltage-dependent calcium channels; this is followed by the activation of potassium-selective channels, so returning the membrane potential towards its ‘resting’ value before a new cycle begins. However, it is now clear that in several tissues, particularly those lying in the gastrointestinal and urinary tracts, activity is not initiated by smooth muscles; rather it is generated by a separate group of cells, known as interstitial cells of Cajal (ICC). ICC are distributed amongst the smooth muscle cells and are electrically connected to neighbouring smooth muscle cells, and hence any activity they produce changes the membrane potential of the nearby smooth muscle cells. In most regions of the gastrointestinal tract, an interconnected network of ICC is located near the myenteric plexus (ICCMY). ICCMY generate pacemaker potentials that conduct passively to the adjacent longitudinal and circular muscle layers where they produce rhythmical waves of membrane depolarization. The waves of depolarization, in turn, activate voltage-dependent calcium channels in the smooth muscle cells and rhythmical mechanical contractions are generated. In several regions of the gastrointestinal tract ICC are distributed amongst the smooth muscle cells, intramuscular ICC (ICCIM), making up the two muscle layers. ICCIM are tightly coupled to the nearby smooth muscle cells and again any electrical activity they generate passively alters the membrane potential of the nearby smooth muscle cells. In some regions of the gut, the activity of ICCIM can be altered by changes in membrane potential, so allowing them to generate waves of electrical activity; in other regions of activity ICCIM lack voltage sensitivity, so allowing the cells only to generate a resting discharge of activity. However, ICCIM throughout the gut are selectively innervated by enteric nerve terminals and activity in the nerves innervating them alters the activity generated by ICCIM. More recently closely related observations have been made using tissues from different regions of the urinary tract. Again activity generated by urinary ICC passively changes the membrane potential of nearby smooth muscle cells and coordinated patterns of mechanical activity are again triggered. The symposium held in Okinawa, in association with Japanese Society for Smooth Muscle Research concentrated on the role of ICC in the control of gastrointestinal and urinary motility. The symposium was introduced by Professor Tadao Tomita, who described the pioneering studies on rhythmical activity generated by smooth muscles, leading up to the idea that ICC played a key role. The idea arose initially from histological studies (Thuneberg, 1982) and shortly afterwards received overwhelming support from experiments carried out on mutant mice which partially lacked ICC. In the small intestine of these mutant animals, where ICCMY were absent, slow waves could not be detected (Ward et al. 1994; Huizinga et al. 1995). Conversely in the stomachs of these animals ICCIM were absent and in these tissues, despite the anatomical presence of enteric nerve terminals, inhibitory and excitatory nerve responses were essentially absent. A detailed description of the distribution and variation in histological structures of ICC in the gastrointestinal tract was provided by Komuro (2006), who detailed their changes in structure and organization in different regions of the gut. In particular the gross organization was described and it was pointed out that ICCMY formed complex structural relationships with myenteric neurones, despite the fact that functional connections between these groups of cells were not detected. Unequivocal structural evidence of the existence of electrical connections between ICC and smooth muscle cells was presented. The subsequent presentation dealt with the way in which gastric ICC coordinated the movement of stomach contents from the corpus towards the gastro-duodenal junction (Hirst & Edwards, 2006). It was suggested that coporal ICCIM provided the dominant pacemaker activity and that this in turn triggered the discharge of pacemaker/driving potentials in the ICCMY network. Such potentials slowly conducted in an anal direction, exciting bands of antral ICCIM to generate slowly descending waves of contraction. Subsequently the novel mechanisms used by gastric ICC to generate waves of electrical activity were described (Suzuki et al. 2006). Activity was shown to arise from the involvement of IP3-dependent internal Ca2+ stores, followed by the activation of ion-selective channels in the membrane of ICC. The talk stressed the important links with cell metabolism, in particular the part played by mitochondria. The divergent roles of gastric ICCIM in the control of gastric motility were described in detail. Gastric ICCIM are the targets of both cholinergic and nitrergic inhibitory nerve terminals within the stomach wall (Ward & Sanders, 2006). Removal or absence of ICCIM results in the functional loss of these important neuronal control mechanisms. Moreover antral ICCIM were suggested to have an additional function as sensors of wall stretch, being able to be excited by radial distension so changing the intrinsic frequency of antral slow waves. The morning session concluded with an elegant description of the effects of disrupting gastrointestinal ICC (Sanders, 2006). Using calcium imaging techniques allowed a description of the patterns of pacemaker conduction through networks of ICCMY. The disruption of such coordinated activity in mutant animals, where lesions in the network were present, allowed an insight into the likely changes in gastrointestinal control mechanisms in disease states. The afternoon session was devoted to the emerging roles played by ICC in different regions of the urinary tract. The session was introduced by an outline of the pioneering studies made in this area, which first identified and characterized the presence of ICC in the urethra (McHale et al. 2006). Convincing physiological evidence was presented that activity generated by ICC was responsible for urethral tone and that impairing the function of urethral ICC leads to a loss of urethral tone. The complex histological and functional organization of the upper renal plexus was described (Lang et al. 2006). Experiments, carried out at the cellular and tissue level, were described which linked the histological distributions of ICC-like cells, atypical smooth muscle cells and smooth muscle cells. The studies suggested that ICC produced the dominant source of rhythmical electrical activity and this was conducted away from the kidney by both atypical and smooth muscle cells. In not all regions of the urogenital tract do ICC function as pacemaker cells. Hashitani (2006) pointed out that in the bladder their role may be simply to aid coordination whereas in the corpus, their role may well be to generate prostaglandins which alter tone and modulate the activity of noradrenaline, released by sympathetic nerve terminals. The symposium closed with a careful description of the cyclic changes in the internal concentration of calcium ions within urethral ICC (Sergeant et al. 2006). Whilst it appeared that changes in internal calcium were key to the generation of activity, the presentation gave a detailed description of the way in which the internal calcium stores were maintained, paying particular attention to the involvement of the sodium–calcium exchanger system. The closing remarks identified the progress made and pointed out that the study of ICC is in its infancy, with countless opportunities remaining available in the area.