AB285. SPR-12 Evidence supporting a pivotal role for intramuscular interstitial cells of Cajal in the generation of pacemaker activity, phasic contractions and tone in the internal anal sphincter

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.

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

Cell and Tissue Research ◽

10.1007/s00441-011-1138-1 ◽

2011 ◽

Vol 344 (1) ◽

pp. 17-30 ◽

Cited By ~ 41

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

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

The Journal of Physiology ◽

10.1113/jp273618 ◽

2017 ◽

Vol 595 (6) ◽

pp. 2021-2041 ◽

Cited By ~ 26

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

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Interstitial Cells of Cajal Modulate the Tone of the Human Internal Anal Sphincter In Vitro

Diseases of the Colon & Rectum ◽

10.1097/01.dcr.0000442896.47732.e8 ◽

2014 ◽

Vol 57 (3) ◽

pp. 370-377 ◽

Cited By ~ 3

Author(s):

Bruno Lorenzi ◽

Alison F. Brading ◽

Neil J. McC. Mortensen

Keyword(s):

Anal Sphincter ◽

Internal Anal Sphincter ◽

Interstitial Cells Of Cajal ◽

Interstitial Cells ◽

Cells Of Cajal

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Effects of Lubiprostone on Pacemaker Activity of Interstitial Cells of Cajal from the Mouse Colon

Korean Journal of Physiology and Pharmacology ◽

10.4196/kjpp.2014.18.4.341 ◽

2014 ◽

Vol 18 (4) ◽

pp. 341 ◽

Cited By ~ 5

Author(s):

Han-Yi Jiao ◽

Dong Hyun Kim ◽

Jung Suk Ki ◽

Kwon Ho Ryu ◽

Seok Choi ◽

...

Keyword(s):

Interstitial Cells Of Cajal ◽

Interstitial Cells ◽

Pacemaker Activity ◽

Mouse Colon ◽

Cells Of Cajal

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Effects of ATP on Pacemaker Activity of Interstitial Cells of Cajal from the Mouse Small Intestine

Chonnam Medical Journal ◽

10.4068/cmj.2018.54.1.63 ◽

2018 ◽

Vol 54 (1) ◽

pp. 63

Author(s):

Il Koo Park ◽

Jin Ho Kim ◽

Chan Guk Park ◽

Man Yoo Kim ◽

Shankar Prasad Parajuli ◽

...

Keyword(s):

Small Intestine ◽

Interstitial Cells Of Cajal ◽

Interstitial Cells ◽

Pacemaker Activity ◽

Mouse Small Intestine ◽

Cells Of Cajal

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Action potential generation in the small intestine of W mutant mice that lack interstitial cells of Cajal

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1996.271.3.g387 ◽

1996 ◽

Vol 271 (3) ◽

pp. G387-G399 ◽

Cited By ~ 21

Author(s):

J. Malysz ◽

L. Thuneberg ◽

H. B. Mikkelsen ◽

J. D. Huizinga

Keyword(s):

Small Intestine ◽

Action Potentials ◽

Interstitial Cells Of Cajal ◽

Interstitial Cells ◽

K Channel ◽

Pacemaker Activity ◽

Channel Blockade ◽

Auerbach’S Plexus ◽

Cells Of Cajal ◽

Auerbach's Plexus

The small intestine of W/Wv mice lacks both the network of interstitial cells of Cajal (ICC), associated with Auerbach's plexus, and pacemaker activity, i.e., it does not generate slow-wave-type action potentials. The W/Wv muscle preparations showed a wide variety of electrical activities, ranging from total quiescence to generation of action potentials at regular or irregular frequency with or without periods of quiescence. The action potentials consisted of a slow component with superimposed spikes, preceded by a slowly developing depolarization and followed by a transient hyperpolarization. The action potentials were completely abolished by L-type Ca2+ channel blockers. W/Wv mice responded to K+ channel blockade (0.5 mM Ba2+ or 10 mM tetraethylammonium chloride) with effects on amplitude, frequency, rate of rise, and duration of the action potentials. In quiescent tissues from W/Wv mice, K+ channel blockade evoked the typical spikelike action potentials. Electron microscopy identified few methylene blue-positive cells in the W/Wv small intestine associated with Auerbach's plexus as individual ICC. Numbers of resident macrophage-like cells (MLC) and fibroblast-like cells (FLC) were significantly changed. Neither FLC nor MLC were part of a network nor did they form specialized junctions with neighboring cells as ICC do. Hence no cell type had replaced ICC at their normal morphological position associated with Auerbach's plexus. ICC were present in W/Wv mice at the deep muscular plexus in normal organization and numbers, indicating that they are not dependent on the Kit protein and do not take part in generation of pacemaker activity.

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Molecular markers expressed in cultured and freshly isolated interstitial cells of Cajal

AJP Cell Physiology ◽

10.1152/ajpcell.2000.279.2.c529 ◽

2000 ◽

Vol 279 (2) ◽

pp. C529-C539 ◽

Cited By ~ 131

Author(s):

Anne Epperson ◽

William J. Hatton ◽

Brid Callaghan ◽

Philip Doherty ◽

Rebecca L. Walker ◽

...

Keyword(s):

Smooth Muscle ◽

Small Intestine ◽

Interstitial Cells Of Cajal ◽

Expression Profiles ◽

Interstitial Cells ◽

Gastric Fundus ◽

Soluble Form ◽

Pacemaker Activity ◽

Murine Small Intestine ◽

Cells Of Cajal

Located within the tunica muscularis of the gastrointestinal (GI) tract are networks of cells known as interstitial cells of Cajal (ICC). ICC are critical for important basic functions of GI motility such as generation and propagation of slow-wave pacemaker activity and reception of regulatory inputs from the enteric nervous system. We have developed a novel procedure to identify and isolate individual ICC from freshly dispersed cell preparations of the murine small intestine and gastric fundus and to determine differential transcriptional expression We have compared the expression profiles of pacemaker ICC isolated from the murine small intestine (IC-MY) and ICC involved in neurotransmission from the gastric fundus (IC-IM). We have also compared expression profiles between ICC and smooth muscle cells (SMC) and between freshly isolated ICC and cultured ICC. Cultured ICC express smooth muscle myosin, whereas freshly dispersed ICC do not. All cell types express muscarinic receptor types M2and M3, neurokinin receptors NK1and NK3, and inhibitory receptor VIP-1, whereas only cultured ICC and SMC express VIP-2. Both cultured and freshly dispersed IC-IM and IC-MY express the soluble form of stem cell factor, whereas SMC from the gastric fundus express only the membrane-bound form.

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

AJP Cell Physiology ◽

10.1152/ajpcell.00361.2004 ◽

2005 ◽

Vol 288 (3) ◽

pp. C710-C720 ◽

Cited By ~ 67

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.

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