Plasticity of electrical pacemaking by interstitial cells of Cajal and gastric dysrhythmias in W/Wv mutant mice

Ördög, Tamás; Baldo, Marjolaine; Danko, Reka; Sanders, Kenton M.

doi:10.1053/gast.2002.37056

Cited by 64 publications

(52 citation statements)

References 33 publications

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“…3 C and D). We wondered whether the antral response to stretch could lead to breakdown in the proximal-to-distal frequency gradient in the stomach (4,5) and disrupt corpus-to-antrum slow-wave propagation. Experiments to test this question were performed on intact gastric sheets, and recordings were made from cells in the corpus and antrum simultaneously to monitor coupling between these regions.…”

Section: Resultsmentioning

confidence: 99%

“…The stomach has a continuous network of ICC-MY from the orad corpus to the pyloric sphincter (1), and samples of muscle removed from each region demonstrate spontaneous activity that is characteristic of pacemaker cells in that region (4). Corpus ICC-MY typically serve as the dominant pacemaker because slow waves occur at the greatest frequency in this region (4,5). Slow waves, initiated in the corpus, actively propagate around and along the length of the stomach and entrain the activity of distal pacemakers.…”

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confidence: 99%

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Interstitial cells of Cajal mediate mechanosensitive responses in the stomach

Won

Sanders

Ward

2005

Proc. Natl. Acad. Sci. U.S.A.

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152

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Changes in motor activity are a basic response to filling of smooth muscle organs. Responses to gastric filling, for example, are thought to be regulated by neural reflexes. Here, we demonstrate a previously uncharacterized aspect of stretch-dependent responses in visceral smooth muscles that is mediated by mechanosensitive interstitial cells of Cajal. Length ramps were applied to the murine antral muscles while recording intracellular electrical activity and isometric force. Stretching muscles by an average of 27 ؎ 1% of resting length resulted in 5 mN of force. Increasing length caused membrane depolarization and increased slow-wave frequency. The responses were dependent on the rate of stretch. Stretch-dependent responses were not inhibited by neuronal antagonists or nifedipine. Increases in slow-wave frequency, but not membrane depolarization, were inhibited by reducing external Ca 2؉ (100 M) and by Ni 2؉ (250 M). Responses to stretch were inhibited by indomethacin (1 M) and were absent in cyclooxygenase II-deficient mice, suggesting that cyclooxygenase II-derived eicosanoids may mediate these responses. Dual microelectrode impalements of muscle cells within the corpus and antrum showed that stretch-induced changes in slow-wave frequency uncoupled proximal-to-distal propagation of slow waves. This uncoupling could interfere with gastric peristalsis and impede gastric emptying. Stretch of antral muscles of W͞W V mice, which lack intramuscular interstitial cells of Cajal, did not affect membrane depolarization or slow-wave frequency. These data demonstrate a previously uncharacterized nonneural stretch reflex in gastric muscles and provide physiological evidence demonstrating a mechanosensitive role for interstitial cells of Cajal in smooth muscle tissues.gastric compliance ͉ pacemaker ͉ stretch ͉ slow waves ͉ propagation

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Interstitial cells of Cajal mediate mechanosensitive responses in the stomach

Won

Sanders

Ward

2005

Proc. Natl. Acad. Sci. U.S.A.

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152

141

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“…5 Studies on ICC isolated from the corpus and antrum suggest that the frequency gradient is coded intrinsically in the ICC from these regions. 6 Previous studies have also demonstrated that pacemaker activity is intrinsic to ICC and is not generated by neural inputs, because neurotoxins, such as tetrodotoxin (TTX), do not inhibit slow waves. 5 There are at least 2 distinct classes of ICC in the stomach.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Gastric Electrical and Mechanical Activity by Cholinesterases in Mice

Worth

Forrest

Peri

et al. 2015

J Neurogastroenterol Motil

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Background/AimsGastric peristalsis begins in the orad corpus and propagates to the pylorus. Directionality of peristalsis depends upon orderly generation and propagation of electrical slow waves and a frequency gradient between proximal and distal pacemakers. We sought to understand how chronotropic agonists affect coupling between corpus and antrum. Methods Electrophysiological and imaging techniques were used to investigate regulation of gastric slow wave frequency by muscarinic agonists in mice. We also investigated the expression and role of cholinesterases in regulating slow wave frequency and motor patterns in the stomach. Results Both acetycholinesterase (Ache) and butyrylcholine esterase (Bche) are expressed in gastric muscles and AChE is localized to varicose processes of motor neurons. Inhibition of AChE in the absence of stimulation increased slow wave frequency in corpus and throughout muscle strips containing corpus and antrum. CCh caused depolarization and increased slow wave frequency. Stimulation of cholinergic neurons increased slow wave frequency but did not cause depolarization. Neostigmine (1 M) increased slow wave frequency, but uncoupling between corpus and antrum was not detected. Motility mapping of contractile activity in gastric muscles showed similar effects of enteric nerve stimulation on the frequency and propagation of slow waves, but neostigmine (＞ 1 M) caused aberrant contractile frequency and propagation and ectopic pacemaking. Conclusions Our data show that slow wave uncoupling is difficult to assess with electrical recording from a single or double sites and suggest that efficient metabolism of ACh released from motor neurons is an extremely important regulator of slow wave frequency and propagation and gastric motility patterns.

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“…Multipolar ICC, which form two-dimensional networks in the myenteric region, on the submucosal border of the circular smooth muscle layer, and within intermuscular septa of phasic GI smooth muscles, play an essential role in phasic contractile activity and peristalsis by generating and propagating electrical slow waves (4,6,12,13,24,26,42). Elongated or bipolar ICC, which are more loosely distributed within bundles of smooth muscle cells (where they form close contacts with varicose processes of enteric motor neurons), mediate excitatory and inhibitory neural inputs to the smooth musculature (45), may amplify slow waves (5), and contribute to vagally mediated mechanoreception (9).…”

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confidence: 99%

“…Damages to ICC networks have been described in congenital and acquired GI disorders including anorectal malformations, Hirschsprung disease, infantile pyloric stenosis, inflammatory bowel disease, diabetic gastroenteropathy, stromal tumors, and paraneoplastic, idiopathic, or "functional" disorders (11,20,23,27,28,32,41). Many of these changes have also been demonstrated in animal models (2,3,19,24,25,34), which provide an exciting opportunity to study the mechanisms and consequences of ICC loss in these diseases. For example, we have demonstrated that disruptions in gastric ICC networks resulting from impaired Kit signaling (25,26) can lead to electrical arrhythmias by interfering with pacemaker entrainment and by remodeling of the ICC pacemaker apparatus (24).…”

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confidence: 99%

Immunomagnetic enrichment of interstitial cells of Cajal

Ördög

Redelman

Horowitz

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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ruptions of networks of interstitial cells of Cajal (ICC), gastrointestinal pacemakers and mediators of neurotransmission, can lead to disordered phasic contractions and peristalsis by reducing and uncoupling electrical slow waves. However, detailed analysis of the ICC network behavior has been hampered by their scarcity, limited accessibility in intact tissues, and contamination with other cell types in culture. Our goal was to develop a simple technique to purify ICC from murine gastrointestinal muscles for functional studies. We identified ICC in live small intestinal muscles or primary cell cultures by Kit immunoreactivity using fluorescent antibodies. Because this technique also labels resident macrophages nonspecifically, parallel studies were performed in which nonfluorescent Kit antibodies and macrophages labeled with fluorescent dextran were used for subtractive analysis of ICC. In both groups, Kit-positive cells were tagged with superparamagnetic antibodies and sorted on magnetic columns. Efficacy was assessed by flow cytometry. ICC enrichment from primary cultures and freshly dissociated tissues was ϳ63-fold and ϳ8-fold, respectively. Unlike the cells derived directly from tissues, cells sorted from cultures frequently yielded extensive, nearly homogenous ICC networks on reseeding. Monitoring oscillations in mitochondrial Ca 2ϩ or membrane potential by imaging revealed spontaneous rhythmicity in these networks. Cells that did not bind to the columns yielded cultures that were depleted of ICC and dominated by smooth muscle cells. In conclusion, immunomagnetic sorting of primary cultures of ICC results in relatively homogenous, functional ICC networks. This technique is less suitable for obtaining ICC from freshly dispersed cells. mouse; Kit; macrophage; pacemaking; fluorescent imaging INTERSTITIAL CELLS OF CAJAL (ICC) are specialized mesenchymal cells located within the tunica muscularis of the gastrointestinal (GI) tract that play critical roles in GI motor functions and their regulation (32). Multipolar ICC, which form two-dimensional networks in the myenteric region, on the submucosal border of the circular smooth muscle layer, and within intermuscular septa of phasic GI smooth muscles, play an essential role in phasic contractile activity and peristalsis by generating and propagating electrical slow waves (4,6,12,13,24,26, 42). Elongated or bipolar ICC, which are more loosely distributed within bundles of smooth muscle cells (where they form close contacts with varicose processes of enteric motor neurons), mediate excitatory and inhibitory neural inputs to the smooth musculature (45), may amplify slow waves (5), and contribute to vagally mediated mechanoreception (9).The discovery that ICC can be identified by expression of the receptor tyrosine kinase Kit [stem cell factor (SCF) receptor, CD117] (13, 21, 39, 42) has led to several studies on the morphology of ICC networks in human GI disorders. Damages to ICC networks have been described in congenital and acquired GI disorders including anorectal ...

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Plasticity of electrical pacemaking by interstitial cells of Cajal and gastric dysrhythmias in W/Wv mutant mice

Cited by 64 publications

References 33 publications

Interstitial cells of Cajal mediate mechanosensitive responses in the stomach

Interstitial cells of Cajal mediate mechanosensitive responses in the stomach

Regulation of Gastric Electrical and Mechanical Activity by Cholinesterases in Mice

Immunomagnetic enrichment of interstitial cells of Cajal

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