scholarly journals ANO1 in intramuscular interstitial cells of Cajal plays a key role in the generation of slow waves and tone in the internal anal sphincter

2017 ◽  
Vol 595 (6) ◽  
pp. 2021-2041 ◽  
Author(s):  
C. A. Cobine ◽  
E. E. Hannah ◽  
M. H. Zhu ◽  
H. E. Lyle ◽  
J. R. Rock ◽  
...  
Keyword(s):  
Anal Sphincter ◽  
Internal Anal Sphincter ◽  
Interstitial Cells Of Cajal ◽  
Interstitial Cells ◽  
Slow Waves ◽  
Cells Of Cajal

Distribution of Interstitial Cells of Cajal in the Internal Anal Sphincter of Patients With Internal Anal Sphincter Achalasia and Hirschsprung Disease

2003 ◽  
Vol 127 (9) ◽  
pp. 1192-1195 ◽  
Author(s):  
Anna Piaseczna Piotrowska ◽  
Valeria Solari ◽  
Prem Puri
Keyword(s):  
Anal Sphincter ◽  
Internal Anal Sphincter ◽  
Interstitial Cells Of Cajal ◽  
Internal Sphincter ◽  
Smooth Muscles ◽  
Hirschsprung Disease ◽  
Interstitial Cells ◽  
Nerve Fibers ◽  
Internal Anal Sphincter Achalasia ◽  
Cells Of Cajal

Abstract Context.—Interstitial cells of Cajal (ICCs) are pacemaker cells in the smooth muscles of the gut. The internal anal sphincter (IAS) is the most caudal part of gastrointestinal tract. It has the important function of maintaining fecal continence. It has been proposed that ICCs in the IAS mediate the inhibitory innervation of the recto-anal reflexes. Objective.—To investigate the distribution of ICCs in the normal IAS and in the IAS of children diagnosed with internal anal sphincter achalasia (IASA) and Hirschsprung disease (HD). Methods.—At the time of IAS myectomy, specimens of the IAS were taken from 8 patients with IASA, 4 patients with HD, and 4 normal controls. All specimens were examined using anti–c-Kit and antiperipherin antibodies; immunolocalization was detected with light microscopy. Density of the ICCs was graded by computerized image analysis. Results.—There was strong peripherin immunoreactivity in the ganglia cells and nerve fibers in the normal IAS. The number of peripherin-positive nerve fibers was markedly reduced in the IAS in patients with IASA. In HD patients, there was lack of peripherin immunoreactivity in the IAS, but hypertrophic nerve trunks stained strongly. Many c-Kit–positive ICCs were present among the muscle fibers and between the muscle bundles in the normal IAS. In HD and IASA patients, ICCs were absent or markedly reduced. Conclusion.—Altered distribution of ICCs in the internal sphincter in IASA and HD may contribute to motility dysfunction in these patients.

scholarly journals Relationship between interstitial cells of Cajal, fibroblast-like cells and inhibitory motor nerves in the internal anal sphincter

2011 ◽  
Vol 344 (1) ◽  
pp. 17-30 ◽  
Author(s):  
Caroline A. Cobine ◽  
Grant W. Hennig ◽  
Masaaki Kurahashi ◽  
Kenton M. Sanders ◽  
Sean M. Ward ◽  
...  
Keyword(s):  
Anal Sphincter ◽  
Internal Anal Sphincter ◽  
Interstitial Cells Of Cajal ◽  
Interstitial Cells ◽  
Motor Nerves ◽  
Cells Of Cajal

Pacemaker potentials generated by interstitial cells of Cajal in the murine intestine

2005 ◽  
Vol 288 (3) ◽  
pp. C710-C720 ◽  
Author(s):  
Yoshihiko Kito ◽  
Sean M. Ward ◽  
Kenton M. Sanders
Keyword(s):  
Interstitial Cells Of Cajal ◽  
Circular Muscle ◽  
Muscle Cells ◽  
Interstitial Cells ◽  
Slow Waves ◽  
Pacemaker Activity ◽  
Dependent Manner ◽  
Plateau Potential ◽  
Pacemaker Potentials ◽  
Cells Of Cajal

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, hyperpolarized ICC-MY and increased the amplitude and d V/d tmax without affecting frequency. Pinacidil hyperpolarized smooth muscle cells and attenuated the amplitude and d V/d tmax of slow waves without affecting frequency. The effects of pinacidil were blocked by glibenclamide (10 μM). These data suggest that slow waves are electrotonic potentials driven by pacemaker potentials. The upstroke component of pacemaker potentials is due to activation of dihydropyridine-resistant Ca2+ channels, and this depolarization entrains pacemaker activity to create the plateau potential. The plateau potential may be due to summation of unitary potentials generated by individual or small groups of pacemaker units in ICC-MY. Entrainment of unitary potentials appears to depend on Ca2+ entry during upstroke depolarization.

scholarly journals Conditional genetic deletion of Ano1 in interstitial cells of Cajal impairs Ca2+ transients and slow waves in adult mouse small intestine

2017 ◽  
Vol 312 (3) ◽  
pp. G228-G245 ◽  
Author(s):  
John Malysz ◽  
Simon J. Gibbons ◽  
Siva A. Saravanaperumal ◽  
Peng Du ◽  
Seth T. Eisenman ◽  
...  
Keyword(s):  
Small Intestine ◽  
Slow Wave ◽  
Interstitial Cells Of Cajal ◽  
Adult Mouse ◽  
Rank Order ◽  
Interstitial Cells ◽  
Slow Waves ◽  
Functional Reserve ◽  
Mouse Small Intestine ◽  
Cells Of Cajal

Myenteric plexus interstitial cells of Cajal (ICC-MY) in the small intestine are Kit+ electrical pacemakers that express the Ano1/TMEM16A Ca2+-activated Cl– channel, whose functions in the gastrointestinal tract remain incompletely understood. In this study, an inducible Cre-LoxP-based approach was used to advance the understanding of Ano1 in ICC-MY of adult mouse small intestine. KitCreERT2/+;Ano1Fl/Fl mice were treated with tamoxifen or vehicle, and small intestines (mucosa free) were examined. Quantitative RT-PCR demonstrated ~50% reduction in Ano1 mRNA in intestines of conditional knockouts (cKOs) compared with vehicle-treated controls. Whole mount immunohistochemistry showed a mosaic/patchy pattern loss of Ano1 protein in ICC networks. Ca2+ transients in ICC-MY network of cKOs displayed reduced duration compared with highly synchronized controls and showed synchronized and desynchronized profiles. When matched, the rank order for Ano1 expression in Ca2+ signal imaged fields of view was as follows: vehicle controls>>>cKO(synchronized)>cKO(desynchronized). Maintenance of Ca2+ transients’ synchronicity despite high loss of Ano1 indicates a large functional reserve of Ano1 in the ICC-MY network. Slow waves in cKOs displayed reduced duration and increased inter-slow-wave interval and occurred in regular- and irregular-amplitude oscillating patterns. The latter activity suggested ongoing interaction by independent interacting oscillators. Lack of slow waves and depolarization, previously reported for neonatal constitutive knockouts, were also seen. In summary, Ano1 in adults regulates gastrointestinal function by determining Ca2+ transients and electrical activity depending on the level of Ano1 expression. Partial Ano1 loss results in Ca2+ transients and slow waves displaying reduced duration, while complete and widespread absence of Ano1 in ICC-MY causes lack of slow wave and desynchronized Ca2+ transients. NEW & NOTEWORTHY The Ca2+-activated Cl− channel, Ano1, in interstitial cells of Cajal (ICC) is necessary for normal gastrointestinal motility. We knocked out Ano1 to varying degrees in ICC of adult mice. Partial knockout of Ano1 shortened the widths of electrical slow waves and Ca2+ transients in myenteric ICC but Ca2+ transient synchronicity was preserved. Near-complete knockout was necessary for transient desynchronization and loss of slow waves, indicating a large functional reserve of Ano1 in ICC. View this article's corresponding video summary at https://youtu.be/cyPtDP0KLY4 .

scholarly journals Na+-K+-Cl− cotransporter (NKCC) maintains the chloride gradient to sustain pacemaker activity in interstitial cells of Cajal

2016 ◽  
Vol 311 (6) ◽  
pp. G1037-G1046 ◽  
Author(s):  
Mei Hong Zhu ◽  
Tae Sik Sung ◽  
Masaaki Kurahashi ◽  
Lauren E. O'Kane ◽  
Kate O'Driscoll ◽  
...  
Keyword(s):  
Slow Wave ◽  
Interstitial Cells Of Cajal ◽  
High Current Density ◽  
Reversal Potential ◽  
Interstitial Cells ◽  
Slow Waves ◽  
Hek293 Cells ◽  
Pacemaker Activity ◽  
Inward Currents ◽  
Cells Of Cajal

Interstitial cells of Cajal (ICC) generate electrical slow waves by coordinated openings of ANO1 channels, a Ca2+-activated Cl− (CaCC) conductance. Efflux of Cl− during slow waves must be significant, as there is high current density during slow-wave currents and slow waves are of sufficient magnitude to depolarize the syncytium of smooth muscle cells and PDGFRα+ cells to which they are electrically coupled. We investigated how the driving force for Cl− current is maintained in ICC. We found robust expression of Slc12a2 (which encodes an Na+-K+-Cl− cotransporter, NKCC1) and immunohistochemical confirmation that NKCC1 is expressed in ICC. With the use of the gramicidin permeabilized-patch technique, which is reported to not disturb [Cl−]i, the reversal potential for spontaneous transient inward currents ( ESTICs) was −10.5 mV. This value corresponds to the peak of slow waves when they are recorded directly from ICC in situ. Inhibition of NKCC1 with bumetanide shifted ESTICs to more negative potentials within a few minutes and reduced pacemaker activity. Bumetanide had no direct effects on ANO1 or CaV3.2 channels expressed in HEK293 cells or L-type Ca2+ currents. Reducing extracellular Cl− to 10 mM shifted ESTICs to positive potentials as predicted by the Nernst equation. The relatively rapid shift in ESTICs when NKCC1 was blocked suggests that significant changes in the transmembrane Cl− gradient occur during the slow-wave cycle, possibly within microdomains formed between endoplasmic reticulum and the plasma membrane in ICC. Recovery of Cl− via NKCC1 might have additional consequences on shaping the waveforms of slow waves via Na+ entry into microdomains.

Are interstitial cells of Cajal plurifunction cells in the gut?

2008 ◽  
Vol 294 (2) ◽  
pp. G372-G390 ◽  
Author(s):  
Sushil K. Sarna
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Interstitial Cells Of Cajal ◽  
Circular Muscle ◽  
Muscle Cells ◽  
Interstitial Cells ◽  
Slow Waves ◽  
Enteric Neurons ◽  
Motility Disorders ◽  
Cells Of Cajal

The proposed functions of the interstitial cells of Cajal (ICC) are to 1) pace the slow waves and regulate their propagation, 2) mediate enteric neuronal signals to smooth muscle cells, and 3) act as mechanosensors. In addition, impairments of ICC have been implicated in diverse motility disorders. This review critically examines the available evidence for these roles and offers alternate explanations. This review suggests the following: 1) The ICC may not pace the slow waves or help in their propagation. Instead, they may help in maintaining the gradient of resting membrane potential (RMP) through the thickness of the circular muscle layer, which stabilizes the slow waves and enhances their propagation. The impairment of ICC destabilizes the slow waves, resulting in attenuation of their amplitude and impaired propagation. 2) The one-way communication between the enteric neuronal varicosities and the smooth muscle cells occurs by volume transmission, rather than by wired transmission via the ICC. 3) There are fundamental limitations for the ICC to act as mechanosensors. 4) The ICC impair in numerous motility disorders. However, a cause-and-effect relationship between ICC impairment and motility dysfunction is not established. The ICC impair readily and transform to other cell types in response to alterations in their microenvironment, which have limited effects on motility function. Concurrent investigations of the alterations in slow-wave characteristics, excitation-contraction and excitation-inhibition couplings in smooth muscle cells, neurotransmitter synthesis and release in enteric neurons, and the impairment of the ICC are required to understand the etiologies of clinical motility disorders.

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