Colonic Transit Disorder Mediated by Downregulation of Interstitial Cells of Cajal/Anoctamin-1 in Dextran Sodium Sulfate-induced Colitis Mice

Interstitial cells of Cajal (ICC) provide pacemaker activity in gastrointestinal muscles that underlies segmental and peristaltic contractions. ICC generate electrical slow waves that are due to large-amplitude inward currents resulting from anoctamin 1 (ANO1) channels, which are Ca2+-activated Cl− channels. We investigated the hypothesis that the Ca2+ responsible for the stochastic activation of ANO1 channels during spontaneous transient inward currents (STICs) and synchronized activation of ANO1 channels during slow wave currents comes from intracellular Ca2+ stores. ICC, obtained from the small intestine of Kit +/copGFP mice, were studied under voltage and current clamp to determine the effects of blocking Ca2+ uptake into stores and release of Ca2+ via inositol 1,4,5-trisphosphate (IP3)-dependent and ryanodine-sensitive channels. Cyclocpiazonic acid, thapsigargin, 2-APB, and xestospongin C inhibited STICs and slow wave currents. Ryanodine and tetracaine also inhibited STICs and slow wave currents. Store-active compounds had no direct effects on ANO1 channels expressed in human embryonic kidney-293 cells. Under current clamp, store-active drugs caused significant depolarization of ICC and reduced spontaneous transient depolarizations (STDs). After block of ryanodine receptors with ryanodine and tetracaine, repolarization did not restore STDs. ANO1 expressed in ICC has limited access to cytoplasmic Ca2+ concentration, suggesting that pacemaker activity depends on Ca2+ dynamics in restricted microdomains. Our data from studies of isolated ICC differ somewhat from studies on intact muscles and suggest that release of Ca2+ from both IP3 and ryanodine receptors is important in generating pacemaker activity in ICC.

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Expression of anoctamin 1/TMEM16A by interstitial cells of Cajal is fundamental for slow wave activity in gastrointestinal muscles

The Journal of Physiology ◽

10.1113/jphysiol.2009.176198 ◽

2009 ◽

Vol 587 (20) ◽

pp. 4887-4904 ◽

Cited By ~ 257

Author(s):

Sung Jin Hwang ◽

Peter J. A. Blair ◽

Fiona C. Britton ◽

Kate E. O’Driscoll ◽

Grant Hennig ◽

...

Keyword(s):

Slow Wave ◽

Interstitial Cells Of Cajal ◽

Interstitial Cells ◽

Wave Activity ◽

Slow Wave Activity ◽

Anoctamin 1 ◽

Cells Of Cajal

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Role of Ano1 Ca2+-activated Cl− channels in generating urethral tone

AJP Renal Physiology ◽

10.1152/ajprenal.00520.2020 ◽

2021 ◽

Vol 320 (4) ◽

pp. F525-F536

Author(s):

Bernard T. Drumm ◽

Keith D. Thornbury ◽

Mark A. Hollywood ◽

Gerard P. Sergeant

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Interstitial Cells Of Cajal ◽

Muscle Cells ◽

Interstitial Cells ◽

Anoctamin 1 ◽

Cl Channels ◽

Experimental Approaches ◽

Cells Of Cajal

Studies from rabbit show that anoctamin-1 (Ano1) channels expressed in urethral interstitial cells of Cajal (ICCs) serve as a source of depolarization for smooth muscle cells, increasing excitability and tone. However, the role of urethral Ano1 channels is unclear, owing to differences in the species examined and experimental approaches. We summarize findings from different species on the role of urethral ICC and Ano1 channels in urethral contractility and outline proposals for clarifying this topic using cell-specific optogenetic approaches.

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Electroacupuncture Regulates Apoptosis/Proliferation of Intramuscular Interstitial Cells of Cajal and Restores Colonic Motility in Diabetic Constipation Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/584179 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Juanjuan Xu ◽

Yan Chen ◽

Shi Liu ◽

Xiaohua Hou

Keyword(s):

High Frequency ◽

Interstitial Cells Of Cajal ◽

Colonic Motility ◽

Low Frequency ◽

Interstitial Cells ◽

Colonic Transit ◽

Immunofluorescent Staining ◽

High Frequency Stimulation ◽

Frequency Stimulation ◽

Cells Of Cajal

Injury of interstitial cells of Cajal (ICC) is associated with gut dysmotility in diabetic rats. We have shown an acceleration of the colonic contractility by electroacupuncture stimulation (EAS). However, little is known about potential roles of EAS on colonic transit and ICC. In this study, we evaluate the effect of EAS on colonic transit and investigate whether apoptosis/proliferation of ICC was involved in regulative effect of EAS on colonic transit. Rats were randomly assigned to normal, diabetic, diabetic-plus-sham stimulation, diabetic-plus-low-frequency stimulation, and diabetic-plus-high-frequency stimulation groups. Bead expulsion test was used for measuring the distal colonic transit. The Kit (ICC marker) was detected by western blot. Apoptotic ICC was detected by terminal dUTP nucleotide end labeling. Proliferating ICC was identified by Kit/Ki67 double immunofluorescent staining on whole mount preparations. Ultrastructure changes of ICC were studied using electron microscopy. Results showed that high-frequency stimulation significantly promoted colonic transit. Low- and high-frequency stimulation markedly rescued intramuscular ICC from apoptosis. Abundant proliferating intramuscular ICC was found in low- and high-frequency stimulation groups. Our results indicate that high-frequency EAS has stimulatory effect on the distal colonic transit, which may be mediated by downregulation of the apoptosis and upregulation of the proliferation of intramuscular ICC.

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Electroacupuncture at Zusanli (ST36) Repairs Interstitial Cells of Cajal and Upregulates c-Kit Expression in Rats with SCI-Induced Neurogenic Bowel Dysfunction

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/8896123 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Yujie Yang ◽

Jie Cheng ◽

Yongni Zhang ◽

Jiabao Guo ◽

Bin Xie ◽

...

Keyword(s):

Interstitial Cells Of Cajal ◽

Bowel Dysfunction ◽

Interstitial Cells ◽

Colonic Transit ◽

Sprague Dawley ◽

Ultrastructural Morphology ◽

Sprague Dawley Rats ◽

Cord Injury ◽

Cells Of Cajal ◽

Neurogenic Bowel

Background. Electroacupuncture (EA) could improve colonic transit activity in rats with neurogenic bowel dysfunction (NBD) caused by spinal cord injury (SCI). The function of interstitial cells of Cajal (ICCs) and c-Kit expression may play essential roles in this process. Material and Methods. Thirty-six Sprague Dawley rats were randomized to the sham group, the SCI group, or the SCI + EA group (bilateral Zusanli, 30 min/day, 14 days). Changes in the ultrastructural morphology of ICCs were observed. The c-Kit expression on different levels was analyzed by immunohistochemistry, Western blotting, and RT-qPCR, respectively. Results. Abnormal morphology of ICCs and downregulation of the c-Kit expression occurred after SCI. While the number of ICCs was increased, the ultrastructural morphology was improved significantly in EA rats. They also showed better improvement in c-Kit expression at both protein and gene levels. Conclusion. Abnormal ICCs in colon tissues and the downregulated expression of c-Kit could be observed after SCI. EA at Zusanli (ST36) could improve the colon function by repairing the morphology and increasing the number of ICCs and upregulating c-Kit expression.

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Electroacupuncture at Acupoint ST-36 Promotes Colonic Transit via Regulating Proliferation/Apoptosis of Interstitial Cells of Cajal in the Colon of Diabetic Rats

Gastroenterology ◽

10.1016/s0016-5085(11)61548-5 ◽

2011 ◽

Vol 140 (5) ◽

pp. S-378-S-379

Author(s):

Juanjuan Xu ◽

Yan Chen ◽

Shi Liu

Keyword(s):

Interstitial Cells Of Cajal ◽

Interstitial Cells ◽

Diabetic Rats ◽

Colonic Transit ◽

Cells Of Cajal

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Computational modeling of anoctamin 1 calcium-activated chloride channels as pacemaker channels in interstitial cells of Cajal

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00449.2013 ◽

2014 ◽

Vol 306 (8) ◽

pp. G711-G727 ◽

Cited By ~ 20

Author(s):

Rachel Lees-Green ◽

Simon J. Gibbons ◽

Gianrico Farrugia ◽

James Sneyd ◽

Leo K. Cheng

Keyword(s):

Slow Wave ◽

Interstitial Cells Of Cajal ◽

Reversal Potential ◽

Interstitial Cells ◽

Slow Waves ◽

Equilibrium Potential ◽

Pacemaker Activity ◽

Anoctamin 1 ◽

Pacemaker Channel ◽

Cells Of Cajal

Interstitial cells of Cajal (ICC) act as pacemaker cells in the gastrointestinal tract by generating electrical slow waves to regulate rhythmic smooth muscle contractions. Intrinsic Ca2+ oscillations in ICC appear to produce the slow waves by activating pacemaker currents, currently thought to be carried by the Ca2+-activated Cl− channel anoctamin 1 (Ano1). In this article we present a novel model of small intestinal ICC pacemaker activity that incorporates store-operated Ca2+ entry and a new model of Ano1 current. A series of simulations were carried out with the ICC model to investigate current controversies about the reversal potential of the Ano1 Cl− current in ICC and to predict the characteristics of the other ion channels that are necessary to generate slow waves. The model results show that Ano1 is a plausible pacemaker channel when coupled to a store-operated Ca2+ channel but suggest that small cyclical depolarizations may still occur in ICC in Ano1 knockout mice. The results predict that voltage-dependent Ca2+ current is likely to be negligible during the slow wave plateau phase. The model shows that the Cl− equilibrium potential is an important modulator of slow wave morphology, highlighting the need for a better understanding of Cl− dynamics in ICC.

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