Regulation of pacemaker frequency in the murine gastric antrum (original) (raw)
Related papers
Neurogastroenterology and Motility, 2004
Considerable work has led many to conclude that interstitial cells of Cajal (ICC) are the pacemaker cells of the gastrointestinal (GI) tract. These cells form electrically coupled networks within the pacemaker regions of the GI tract, and ICC are electrically coupled to smooth muscle cells. ICC express unique ion channels that periodically produce inward (pacemaker) currents. Recent work has suggested that the inward current is produced by a calcium (Ca 2+ )-regulated, nonselective cation conductance. Channels responsible for this conductance oscillate in open probability in response to the periodic drop in intracellular Ca 2+ concentration during the slow wave cycle. Pacemaker activity generates slow waves that are propagated actively through ICC networks. Depolarization coordinates the pacemaker activity through the ICC network by activating a dihydropyridine-resistant Ca 2+ conductance. Entry of small amounts of Ca 2+ into ICC entrains spontaneous pacemaker activity and produces cell-to-cell propagation of slow waves. This review discusses the mechanisms and conductances involved in generation and propagation of electrical slow waves in ICC.
Distribution of pacemaker function through the tunica muscularis of the canine gastric antrum
The Journal of Physiology, 2001
Interstitial cells of Cajal (ICC) are found at specific locations within the tunica muscularis of the gastrointestinal (GI) tract. Studies performed on tissues of the mouse and guinea-pig have suggested that ICC in different anatomical locations have discrete physiological roles. Studies in the mouse have been aided by the fact that ckit and stem cell factor mutant animals fail to develop certain types of ICC, and specific functional losses have been observed in these animals (Ward et al. 1994, 1995; Huizinga et al. 1995; Burns et al. 1996). For example, when ICC in the myenteric region of the small intestine (IC-MY) are lost, slow wave activity is not present, suggesting that IC-MY are pacemaker cells (Ward et al. 1994; Huizinga et al. 1995). When intramuscular ICC of the stomach and lower oesophageal and pyloric sphincters are lost, neural inputs from the enteric nervous system are greatly reduced, suggesting these cells are important mediators of neurotransmission (Burns et al. 1996; Ward et al. 1998, 2000a). Studies with neutralizing antibodies to Kit protein have supported the idea that IC-MY are pacemaker cells (Torihashi et al. 1995) and demonstrated that these cells are also needed for active propagation of slow waves in the small bowel and stomach (Ordog et al. 1999). Thus, a picture has emerged regarding the functional significance of ICC in the GI tract, and these studies have suggested that a 'division of labour' exists between pacemaker ICC (IC-MY) and ICC involved in neurotransmission (IC-IM in the stomach and IC-DMP in the small intestine: see Sanders et al. 1999). The concept that electrical slow waves originate in ICC, actively propagate in ICC, and passively spread into electrically coupled smooth muscle cells is supported by
A Novel Pacemaker Mechanism Drives Gastrointestinal Rhythmicity
News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society, 2000
Electric pacemaker activity drives peristaltic and segmental contractions in the gastrointestinal tract. Interstitial cells of Cajal (ICC) are responsible for spontaneous pacemaker activity. ICC remain rhythmic in culture and generate voltage-independent inward currents via a nonselective cation conductance. Ca(2+) release from endoplasmic reticulum and uptake by mitochondria initiates pacemaker currents. This novel mechanism provides the basis for electric rhythmicity in gastrointestinal muscles.
Pacemaker potentials generated by interstitial cells of Cajal in the murine intestine
AJP: Cell Physiology, 2004
Pacemaker potentials were recorded in situ from myenteric interstitial cells of Cajal (ICC-MY) in the murine small intestine. The nature of the two components of pacemaker potentials (upstroke and plateau) were investigated and compared with slow waves recorded from circular muscle cells. Pacemaker potentials and slow waves were not blocked by nifedipine (3 μM). In the presence of nifedipine, mibefradil, a voltage-dependent Ca2+ channel blocker, reduced the amplitude, frequency, and rate of rise of upstroke depolarization (d V/d tmax) of pacemaker potentials and slow waves in a dose-dependent manner (1–30 μM). Mibefradil (30 μM) changed the pattern of pacemaker potentials from rapidly rising, high-frequency events to slowly depolarizing, low-frequency events with considerable membrane noise (unitary potentials) between pacemaker potentials. Caffeine (3 mM) abolished pacemaker potentials in the presence of mibefradil. Pinacidil (10 μM), an ATP-sensitive K+ channel opener, hyperpolari...
AJP: Cell Physiology, 2005
Spontaneous electrical pacemaker activity occurs in tunica muscularis of the gastrointestinal (GI) tract and drives phasic contractions. Interstitial cells of Cajal (ICC) are the pacemaker cells that generate and propagate electrical slow waves. We used Ca 2+ imaging to visualize spontaneous rhythmicity in ICC in the myenteric region (ICC-MY) of the murine small intestine. ICC-MY, verified by co-labeling with Kit antibody, displayed regular Ca 2+ transients that occurred after electrical slow waves. ICC-MY formed networks, and Ca 2+ transient wavefronts propagated through the ICC-MY networks at approximately 2 mm.s -1 and activated attached longitudinal muscle (LM) fibers. Nicardipine blocked Ca 2+ transients in LM, but had no visible effect on the transients in ICC-MY. ß-Glycyrrhetinic acid (ß-GA) reduced the coherence of propagation, causing single cells to pace independently. Thus, virtually all ICC-MY are spontaneously active, but normal activity is organized into propagating wavefronts. Inhibitors of dihydropyridine-resistant Ca 2+ entry (Ni 2+ and mibefradil) and elevated external K + reduced the coherence and velocity of propagation, eventually blocking all activity. The mitochondrial uncouplers, carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and antimycin and IP 3 receptor inhibitory drug, 2-Aminoetoxydiphenyl borate (2-APB) abolished rhythmic Ca 2+ transients in ICC-MY. These data show that global Ca 2+ transients in ICC-MY are a reporter of electrical slow waves in GI muscles. Imaging of ICC networks provides a unique multicellular view of pacemaker activity. The activity of ICC-MY is driven by intracellular Ca 2+ handling mechanisms and entrained by voltagedependent Ca 2+ entry and coupling of cells via gap junctions. (236 words) 2 C -0 0 4 4 7 -2 0 0 5 . R 2 18751. NJS was also supported by P20 RR-18751. 22 C -0 0 4 4 7 -2 0 0 5 . R 2
Muscarinic regulation of pacemaker frequency in murine gastric interstitial cells of Cajal
The Journal of Physiology, 2003
Gastric peristaltic waves originate near the greater curvature of the corpus and spread towards the pylorus (Kelly & Code, 1971). These events are important in the mixing and trituration of ingested food. Peristaltic contractions are timed by the occurrence of electrical slow waves, and depend upon the orderly propagation of slow waves from corpus to pylorus (see Szurszewski, 1987). Each region of the stomach distal to the orad corpus is capable of generating spontaneous electrical slow waves, but there is an intrinsic frequency gradient from the proximal to the distal stomach in which slow waves occur at a higher frequency in the proximal stomach (e.g. 3.7 cycles min _1 in the human corpus) than in the distal stomach (1.4 cycles min _1 in the mid-antrum; El-Sharkawy et al. 1978, but see also Kelly & Code, 1971; Sarna et al. 1972, 1976). The corpus pacemaker is dominant because slow waves are generated at the highest frequency in this region. Active propagation of slow waves from the corpus entrains more distal pacemakers because there is time for a corpus slow wave to propagate to the antrum and activate the pacemaker mechanism before it discharges spontaneously (Kelly & Code, 1971; Sarna et al. 1972). Disruption in the gastric slow-wave frequency gradient can lead to failure of the normal corpus-to-pylorus propagation of slow waves and interfere with gastric emptying. For example, if the antral slow-wave frequency rises, entrainment by the corpus pacemaker may fail because antral events may occur before events can propagate from the corpus. Under these conditions, both regions manifest pacemaker activity, but 'functional uncoupling' can occur between gastric regions due to disruption in the proximalto-distal frequency gradient. There are numerous reports in the literature linking gastric motility disorders, dyspepsia, gastroparesis, chronic nausea and vomiting to defects in slow-wave frequency and propagation and the development of ectopic pacemaker activity in the distal stomach (e.g.
Interstitial cells of Cajal generate electrical slow waves in the murine stomach
The Journal of Physiology, 1999
Interstitial cells of Cajal (ICC) are small spindle-shaped or stellate cells with numerous mitochondria and long processes that form networks between and within smooth muscle layers in the gastrointestinal (GI) tract (Thuneberg, 1982; Sanders, 1996). Populations of ICC are found in pacemaker regions of gastrointestinal muscles (Suzuki et al. 1986; Berezin et al. 1988). Isolated ICC are electrically rhythmic and express ionic conductances consistent with a role in pacemaking (Langton et al. 1989; Lee & Sanders, 1993). More recent studies have shown that ICC retain electrical rhythmicity in culture via generation of spontaneous transient inward currents (