Blockade of kit signaling induces transdifferentiation of interstitial cells of cajal to a smooth muscle phenotype.

BACKGROUND & AIMS: Interstitial cells of Cajal (ICC) serve as pacemaker cells and mediators of neurotransmission from the enteric nervous system to gastrointestinal muscles. ICC develop from mesenchymal cells that express c-Kit, and signaling via Kit receptors is necessary for normal development of ICC. We studied the fate of functionally developed ICC after blockade of Kit receptors to determine whether ICC undergo cell death or whether the phenotype of the cells is modified. The fate of undeveloped ICC was also investigated. METHODS: Neutralizing, anti-Kit monoclonal antibody (ACK2) was administered to mice for 8 days after birth. ICC in the small intestine were examined by immunohistochemistry and electron microscopy. Occurrence of apoptosis was also assayed. RESULTS: When Kit receptors were blocked, ICC nearly disappeared from the small intestine. Apoptosis was not detected in regions where ICC are normally distributed. Remaining Kit-immunopositive cells in the pacemaker region of the small intestine developed ultrastructural features similar to smooth muscle cells, including prominent filament bundles and expression of the muscle-specific intermediate filament protein, desmin, and smooth muscle myosin. ICC of the deep muscular plexus normally develop after birth in the mouse. Precursors of these cells remained in an undifferentiated state when Kit was blocked. CONCLUSIONS: These data, along with previous studies showing that ICC in the pacemaker region of the small intestine and longitudinal muscle cells develop from the same Kit-immunopositive precursor cells, suggest inherent plasticity between the ICC and smooth muscle cells that is regulated by Kit-dependent cell signaling.     

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

BACKGROUND & AIMS: Interstitial cells of Cajal (ICC) generate and propagate slow waves in the stomach. Gastric peristalsis depends on a proximal-to-distal gradient in slow wave frequency. We tested whether the gastric frequency gradient was an intrinsic property of ICC and whether dysrhythmias result from disruptions of ICC networks. METHODS: We studied wild-type (WT) and W/W(V) mice, which have only myenteric (pacemaker) ICC in the stomach. ICC distributions were analyzed by Kit immunofluorescence. Pacemaking in tissues was studied by intracellular electrophysiologic recording and in cultured ICC by monitoring mitochondrial [Ca(2+)] oscillations with rhod-2 fluorescence or membrane potential with DiBAC(4)(3) fluorescence. RESULTS: Slow wave frequencies were constant throughout WT gastric muscle sheets containing corpus and antrum. Separating the antrum from the corpus caused a significant drop in antral slow wave frequency. ICC from WT antrums also displayed significantly slower pacemaker frequencies than corpus ICC, but the corpus pacemaker frequency dominated in cocultures of corpus and antrum ICC. Myenteric ICC networks were reduced in W/W(V) mice, particularly in the corpus. In W/W(V) mice, separating the antrum from the corpus failed to reduce antral slow wave frequency. Antral pacemaker frequency in ICC from W/W(V) stomachs was the same as in corpus ICC. CONCLUSIONS: The proximal-to-distal slow wave frequency gradient and entrainment of distal electrical activity by proximal pacemakers are fundamental properties of gastric ICC. Chronic depletion of ICC networks disrupts the proximal-to-distal frequency gradient, and emergence of ectopic pacemakers in the antrum may be caused by "reprogramming" of the ICC pacemaker apparatus.     

A deficiency of gastric interstitial cells of Cajal accompanied by decreased expression of neuronal nitric oxide synthase and substance P in patients with type 2 diabetes mellitus

Background Gastrointestinal motility is impaired in patients with diabetes mellitus (DM). Interstitial cells of Cajal (ICC) in the gastrointestinal tract play a central role in gastrointestinal motility. The present study examined whether ICC density, or expression of neuronal nitric oxide synthase (nNOS)- and substance P (SP)-containing nerves in the gastric antrum, were altered in patients with type 2 DM. Methods Paraffin-embedded gastric specimens from 51 controls and 36 male DM patients with gastric cancer were used for immunohistochemistry. Serial sections were stained with Kit and mast cell tryptase-specific antibodies. Fresh-frozen gastric specimens from patients with gastric cancer were used for immunofluorescence. The specimens were stained with antibodies to Kit, nNOS, and SP, and levels of expression of these three markers were compared between controls and DM patients. Results ICC density in the inner circular muscle layer, but not in the myenteric plexus, was lower in patients with severe DM than in controls in paraffin-embedded specimens. In addition, decreased expression of nNOS and SP accompanied by reduced ICC density was observed in frozen specimens from patients with DM. Conclusions These results suggest that lower gastric ICC, nNOS, and SP densities in patients with DM may be associated with the pathogenesis of diabetic gastroparesis.     

Gastric myoelectrical activity in patients with gastric outlet obstruction and idiopathic gastroparesis

Objective: The cause of gastroparesis may be uncertain in some patients. Mechanical obstruction of the stomach or duodenum should be excluded in patients with idiopathic gastroparesis. The objective of this study was to compare gastric myoelectrical activity in patients with idiopathic gastroparesis with that of patients with gastroparesis due to mechanical obstruction of the stomach or duodenum.
Methods: Electrogastrography techniques were used to record gastric myoelectrical activity in 20 patients with idiopathic gastroparesis and in nine patients with gastroparesis secondary to gastric outlet obstruction. Four of these nine patients initially were thought to have idiopathic gastroparesis. Electrogastrograms (EGGs) were recorded from 29 healthy subjects who served as controls. EGGs were recorded for 20–30 min 2 h after a standard 200-Kcal meal and were analyzed visually and by computer.
Results: Patients with gastroparesis due to outlet obstruction had high-amplitude and excessively regular 3–cycles-per-minute (cpm) EGG patterns, whereas patients with idiopathic gastroparesis had primarily 1- to 2-cpm patterns and little 3-cpm EGG activity. The percentage of total EGG power in the 3-cpm range was approximately 50% in patients with gastric outlet obstruction compared with 20% in patients with idiopathic gastroparesis (   p < 0.001  ). The percentage of EGG power in the normal 3-cpm range was greater in the obstructed patients (50%) than in the healthy controls (35%;   p < 0.052  ).
Conclusions: Gastric myoelectrical patterns recorded in the EGG distinguish mechanical and idiopathic causes of gastroparesis and may be useful in evaluating patients with nausea, vomiting, and gastroparesis of unknown cause.     

Development of interstitial cells of Cajal and pacemaking in mice lacking enteric nerves.

BACKGROUND & AIMS: Development of interstitial cells of Cajal (ICC) requires signaling via Kit receptors. Kit is activated by stem cell factor (SCF), but the source of SCF in the bowel wall is unclear and controversy exists about whether enteric neurons express the SCF required for ICC development. METHODS: Glial cell line-derived neurotrophic factor (GDNF) knockout mice, which lack enteric neurons throughout most of the gut, were used to determine whether neurons are necessary for ICC development. ICC distributions were determined with Kit immunofluorescence, and function of ICC was determined by intracellular electrical recording. RESULTS: ICC were normally distributed throughout the gastrointestinal tracts of GDNF-/- mice. Intracellular recordings from aganglionic gastrointestinal muscles showed normal slow wave activity at birth in the stomach and small intestine. Slow waves developed normally in aganglionic segments of small bowel placed into organ culture at birth. Quantitative polymerase chain reaction showed similar expression of SCF in the muscles of animals with and without enteric neurons. Expression of SCF was demonstrated in isolated intestinal smooth muscle cells. CONCLUSIONS: These data suggest that enteric neurons are not required for the development of functional ICC. The circular smooth muscle layer, which develops before ICC, may be the source of SCF required for ICC development.     

Gastric electrical stimulation for the treatment of diabetic gastroparesis

Diabetic gastroparesis is a component of autonomic neuropathy, and is the most common manifestation of gastrointestinal neuropathy. Diabetes is responsible for about one quarter of gastroparesis. The upper gastrointestinal symptoms are often non-specific and dominated by nausea, vomiting, early satiety, fullness, bloating. We also have to look for diabetic gastroparesis in case of metabolic instability, such as postprandial hypoglycaemia. The pathophysiology of diabetic gastroparesis is complex, partly due to a vagus nerve damage, but also to changes in secretion of hormones such as motilin and ghrelin. A decrease in the stem cell factor (SCF), growth factor for cells of Cajal (gastric pacemaker), was found in subjects with diabetic gastroparesis. These abnormalities lead to an excessive relaxation in the corpus, a hypomotility of antrum, a desynchronization antrum-duodenum-pylorus, and finally an abnormal duodenal motility. The treatment of diabetic gastroparesis is based on diabetes control, and split meals by reducing the fiber content and fat from the diet. The antiemetic and prokinetic agents should be tested primarily in people with nausea and vomiting. Finally, after failure of conventional measures, the use of gastric neuromodulation is an effective alternative, with well-defined indications. Introduced in the 1970s, this technology works by applying electrical stimulation continues at the gastric antrum, particularly in patients whose gastric symptoms are refractory to other therapies. Its efficacy has been recently reported in different causes of gastroparesis, especially in diabetes. Gastric emptying based on gastric scintigraphy, gastrointestinal symptoms, biological markers of glycaemic control and quality of life are partly improved, but not normalized. Finally, a heavy nutritional care is sometimes necessary in the most severe forms. The enteral route should be preferred (nasojejunal and jejunostomy if possible efficiency). However, in case of failure especially in patients with small bowel neuropathy, the long-term parenteral nutrition is sometimes required.     

胰岛素、干细胞因子和Cajal间质细胞在糖尿病胃轻瘫中的作用

糖尿病胃轻瘫是糖尿病的常见并发症，严重影响患者的生活质量和血糖控制。胃肠道Cajal间质细胞在维持胃肠功能中发挥重要作用，糖尿病智组织中存在Cajal间质细胞数量和结构的异常改变，从而影响胃动力。胰岛素、干细胞因子对糖尿病胃肠道Cajal间质细胞的病变具有重要调控作用。本文就胰岛素、干细胞因子和Cajal间质细胞在糖尿病胃轻瘫中的作用作一综述。     

Ultrastructure of interstitial cells of Cajal at the colonic submuscular border in patients with ulcerative colitis

BACKGROUND & AIMS: Submuscular interstitial cells of Cajal (ICC) are putative pacemaker cells of the colonic external muscle. Although motility disturbances and smooth muscle dysfunction are prevalent in patients with ulcerative colitis (UC), ICC have never been studied in this disease. The aim of this study was to examine the ultrastructure of submuscular ICC in UC. METHODS: Transmission electron microscopy of the colonic submuscular region was performed using specimens from 4 adult patients who had undergone resection for severe UC. The specimens were compared with similarly processed control samples. RESULTS: ICC often showed multiple secondary lysosomes, large confluent lipid bodies, and disrupted aggregates of vacuolated glycogen clusters. Intermediate filaments showed margination and clumping. Intramuscular and submucosal nerve terminals were often swollen. Macrophages were frequent, often close to nerves and ICC. Muscle cells of the innermost circular layer, fibroblast-like cells, and glial cells appeared undisturbed. Other inflammatory cells were inconspicuous. CONCLUSIONS: Alterations of ICC ultrastructure are present in the submuscular pacemaker region of the colon in patients with severe UC. The changes in ICC may result from primary damage or changes secondary to defective muscular function, or they may reflect neuroimmune-mediated metabolic responses. It is suggested that ICC are actively involved in the pathogenesis of motility disturbances in UC. (Gastroenterology 1996 Dec;111(6):1447-55)     

Severe idiopathic gastroparesis due to neuronal and interstitial cells of Cajal degeneration: pathological findings and management

Delayed gastric emptying can be due to muscular, neural, or humoral abnormalities. In the absence of an identified cause, gastroparesis is labelled as idiopathic. We present the case of a patient with severe idiopathic gastroparesis. Pharmacological approaches failed, as well as reduction in gastric emptying resistance with pyloric injection of botulinum toxin and pyloroplasty. Therefore, subtotal gastrectomy was performed. Histological and immunohistochemical study of the resected specimen showed hypoganglionosis, neuronal dysplasia, and a marked reduction in both myenteric and intramuscular interstitial cells of Cajal. To our knowledge, this is the first time these rare histological findings have been described in a patient with idiopathic gastroparesis.     

Treatment of idiopathic gastroparesis with injection of botulinum toxin into the pyloric sphincter muscle

OBJECTIVES: We aimed to determine if botulinum toxin injection into the pyloric sphincter improves gastric emptying and reduces symptoms in patients with idiopathic gastroparesis. METHODS: Patients with idiopathic gastroparesis not responding to prokinetic therapy underwent botulinum toxin (80-100 U, 20 U/ml) injection into the pyloric sphincter. Gastric emptying scintigraphy was performed before and 4 wk after treatment. Total symptom scores were obtained from the sum of eight upper GI symptoms graded on a scale from 0 (none) to 4 (extreme). RESULTS: Ten patients were entered into the study. The mean percentage of solid gastric retention at 4 h improved from 27+/-6% (normal < 10%) before botulinum toxin injection into the pylorus to 14+/-4% (p = 0.038) 4 wk after treatment. The symptom score decreased from 15.3+/-1.7 at baseline to 9.0+/-1.9 (p = 0.006) at 4 wk, a 38+/-9% decrease. Improvement in symptoms tended to correlate with improved gastric emptying of solids (r = 0.565, p 0.086). CONCLUSIONS: This initial pilot study suggests that botulinum toxin injection into the pylorus in patients with idiopathic gastroparesis improves both gastric emptying and symptoms.     

Pathophysiology of idiopathic gastroparesis and implications for therapy

Objectives: Idiopathic gastroparesis is a gastric motility disorder characterized by chronic upper gastrointestinal symptoms and delayed gastric emptying without an identifiable underlying condition. This review summarizes recent understanding of the pathophysiology and treatment of idiopathic gastroparesis.

Materials and methods: Structured literature search in the PubMed, Embase and ClinicalTrials.gov databases.

Results: Idiopathic gastroparesis involves several alterations in gastric motility and sensation, including delayed gastric emptying, altered myoelectrical activity, impaired fundic accommodation, visceral hypersensitivity and disturbances in antropyloroduodenal motility and coordination. Multiple cellular changes have been identified, including depletion of interstitial cells of Cajal (ICC) and enteric nerves, as well as stromal fibrosis. The underlying cause of these changes is not fully understood but may be an immune imbalance, including loss of anti-inflammatory heme-oxygenase-1 positive (HO-1) macrophages. There is currently no causal therapy for idiopathic gastroparesis. The treatment ladder consists of dietary measures, prokinetic and antiemetic medications, and varying surgical or endoscopic interventions, including promising pyloric therapies. There are ongoing trials with several novel medications, raising hopes for future treatment.

Conclusions: Patients with idiopathic gastroparesis present several pathophysiological alterations in the stomach, where depletion of ICC is of special importance. Treatment is currently focused on alleviating symptoms through dietary adjustments, medication or surgical or endoscopic interventions.     

糖尿病胃轻瘫大鼠胃窦内ICC和SP变化的实验研究

目的观察Cajal间质细胞和P物质在糖尿病胃轻瘫大鼠胃窦的改变,进而探讨糖尿病胃轻瘫发生的相关机制。方法SD大鼠30只,随机分为正常对照组（n=10）和糖尿病组（n=20）。用链脲佐菌素建立大鼠糖尿病胃轻瘫模型,3个月后用放射性核素（^99Tc）灌胃测定大鼠胃液体排空率,取正常对照组及模型组大鼠胃窦标本,应用免疫组化染色法检测c—kit阳性Cajal间质细胞和P物质在大鼠胃窦的变化,应用彩色病理图像分析软件进行分析,并行统计学比较。结果与正常大鼠相比,糖尿病大鼠胃排空明显延迟（P〈0．01）,胃窦c—kit阳性Cajal间质细胞减少（P〈0．01）,P物质表达减少（P〈0．01）。结论糖尿病胃轻瘫与Cajal间质细胞和P物质的变化有一定的相关性。     

Clinical application prospects of gastric pacing for treating postoperative gastric motility disorders

Similar to the heartbeat, gastric peristalsis is regulated by an electrical rhythm generated by a pacemaker. Thus, electrical dysrhythmia of gastric slow waves will inevitably affect gastric peristalsis and emptying. The recurrence of postoperative gastroparesis is thereby closely related to the abnormalities of electrical dysrhythmia and ectopic pacemakers, resulting in postoperatively persistent gastric motility disorders in some severe cases, despite the use of prokinetic and antiemetic drugs. Recent studies have demonstrated that gastric pacing, analogous to pacing the human heart, is an attractive and promising therapy that is both feasible and safe. Gastric pacing has been shown to be strikingly effective in normalizing gastric dysrhythmia, increasing the activity of the gastric slow wave and thereby prompting gastric dynamia and emptying. Furthermore, the long-term utilization of gastric pacing can (i) relieve patients from clinical symptoms, such as nausea and vomiting; (ii) release patients with severe postoperative gastroparesis from relying on prokinetic drugs and the jejunal feeding tube; (iii) return patients to normal oral nutritional intake and provide a more satisfactory nutritional status and most importantly; and (iv) give patients a better quality of life. Overall, research focused on gastric pacing has demonstrated excellent prospects for clinical application in the treatment of postoperative gastroparesis disorders, especially for those unresponsive to prokinetic drugs.     

Interstitial cells of cajal and inflammation-induced motor dysfunction in the mouse small intestine

BACKGROUND & AIMS: Interstitial cells of Cajal (ICC) play an important role in the control of gastrointestinal motility. We aimed to determine a potential role for ICC in the pathophysiology of inflammation-induced motor disorders. METHODS: Effects of Trichinella spiralis infection on electrical pacemaker activity, the structure of ICC associated with Auerbach's plexus, and in vivo motor patterns were studied in the mouse small intestine. RESULTS: Between days 1 and 15 after infection, structural damage occurred in the network of ICC, particularly in the processes connecting ICC to each other and to smooth muscle cells. This was associated with desynchronization of electrical pacemaker activity. Abnormal slow wave activity occurred, including doubling of frequency and electrical quiescence, leading to the development of ectopic pacemaker activity in vivo. In vivo motor patterns in the small intestine changed from consistent peristaltic contractile activity in control animals to periods of quiescence alternating with both orally and aborally propagating contractile activity in the presence of inflammation. Sixty days after infection, all parameters studied had returned to normal values. CONCLUSIONS: Inflammation-induced alterations in the network of ICC of the small intestine associated with Auerbach's plexus lead to disorganization of motor patterns. Because of the strong temporal correlation between damage to the ICC network, electrical uncoupling, the appearance of ectopic pacemaker activity, and the occurrence of retrograde peristalsis, it is concluded that ICC can play a major role in inflammation-induced motor disturbances.     

Severe gastroparesis: new treatment alternatives

Dopamine antagonists, such as metoclopramide and domperidone, and the motilin receptor agonist erythromycin have been the cornerstones in drug treatment of severe gastroparesis for more than a decade. No new drugs have been approved for treatment of this disorder in this period. Instead, the 5-HT4 agonist cisapride has been withdrawn due to side-effects. The effectiveness of intrapyloric botulinum toxin for gastroparesis remains to be shown. In the last decade, gastric electrical stimulation (GES) with a fully implantable device has evolved as a promising treatment, with significant effects on nausea and vomiting in most patients with severe, drug-refractory diabetic gastroparesis and postsurgical gastroparesis. A proportion of patients with severe idiopathic gastroparesis and patients with idiopathic nausea and vomiting also respond. More research is needed to achieve precise selection of responders/non-responders to GES, and to study the potential benefit of GES in other patient groups suffering from severe nausea or vomiting.     

Ischemic gastroparesis: resolution after revascularization

Patients with chronic nausea and vomiting frequently present challenging diagnostic and therapeutic problems. In such patients, gastroparesis of unknown cause, or "idiopathic" gastroparesis, may be the only objective finding. Two middle-aged women with nausea, vomiting, and weight loss of 10 and 26 kg over 6 and 18 months, respectively, were evaluated. Routine laboratory and barium study results were normal. Solid-phase gastric emptying studies showed severe gastroparesis in both patients. Upper endoscopies excluded gastric outlet obstruction. Gastric dysrhythmias (4-cpm and 1-cpm patterns) were recorded using cutaneous electrodes. An abdominal bruit was ascultated in one patient. Abdominal arteriograms in both patients showed total occlusion of all three major mesenteric vessels with collaterals supplied via hemorrhoidal arteries. Bypass grafting procedures of the celiac and superior mesenteric arteries in one patient and of the celiac artery in the other patient were performed. Six months after mesenteric artery revascularization, upper gastrointestinal symptoms had resolved and original weights were regained. Furthermore, normal 3-cpm gastric myoelectrical activity and normal gastric emptying of solids were restored in both patients. In these patients, chronic mesenteric ischemia resulted in a novel and reversible cause of gastroparesis, gastric dysrhythmias, and accompanying symptoms.     

Electrogastrography in patients with gastroparesis and effect of long-term cisapride

Abnormalities in the gastric pacemaker potentials occur in patients with impaired gastric emptying. It is unclear if treatment effects the underlying rhythm or if normalization of dysrhythmias is important. We examined the effect of cisapride using surface electrogastrograms and radionuclide gastric emptying studies of patients with idiopathic and diabetic gastroparesis. Twelve of 14 patients had abnormal baseline electrogastrograms. After six months of cisapride, four patients had normalization of their electrical activity and six had improvement. Patients with idiopathic gastroparesis had an increase in gastric emptying at 120 min from 48.9±3.8% (baseline) to 70.9±6.0% (six months), P =0.009. Patients with diabetes mellitus had a similar improvement. Patients who had normalization of the electrogastrogram had a greater gastric emptying rate than patients with continued dysrhythmias. Thus, dysrhythmias are important in the etiology for gastroparesis, but other factors need to be examined.This work was in part supported by the Measey Foundation, by NIH grant R01-DK389641-01 A1, and by the Janssen Research Foundation.     

Homing of the bone marrow-derived interstitial cells of Cajal is decreased in diabetic mouse intestine

Background: Interstitial cells of Cajal (ICCs), which express c‐Kit receptor tyrosine kinase (KIT), play an important role in gastrointestinal motility. Loss of ICCs likely contributes to diabetic gastrointestinal motility disorder, however, the mechanism of attrition remains unknown. Here, we test the hypothesis that the bone marrow‐derived progenitors are an important source of intestinal ICCs and that decreased homing of these progenitors in diabetes contributes to ICC diminution. Methods: Wild type mice were X‐ray irradiated, transplanted with bone marrow (BMT) from green fluorescence protein (GFP)‐transgenic (TG)‐mice and subsequently made diabetic by streptozotocin (STZ) injection. Intestinal homing of GFP‐positive bone marrow‐derived cells was examined 2 or 5 months after STZ treatment. Results: In the BMT‐mice, we found many GFP‐positive bone marrow‐derived cells (BMDCs) in most parts of the intestinal area, the number of BMDCs was significantly decreased in diabetic mice compared with nondiabetic controls. As a representative area, we further examined the myenteric plexus of the proximal small intestine, and found that the cell numbers of ICCs marked by c‐Kit‐positive immunoreactivity were decreased by more than 40% in diabetic versus nondiabetic mice. Furthermore, numbers of c‐Kit+/GFP+ and c‐Kit+/GFP‐ cells were similar in nondiabetic mice, and decreased by 45.8% and 42.0%, respectively, in diabetic mice. Conclusion: These results suggest that the decreased homing from the bone marrow is a major cause of ICC loss in the intestine in diabetes mellitus.     

The mechanism and spread of pacemaker activity through myenteric interstitial cells of Cajal in human small intestine

BACKGROUND & AIMS: It has been generally assumed that interstitial cells of Cajal (ICC) in the human gastrointestinal tract have similar functions to those in rodents, but no direct experimental evidence exists to date for this assumption. This is an important question because pathologists have noted decreased numbers of ICC in patients with a variety of motility disorders, and some have speculated that loss of ICC could be responsible for motor dysfunction. Our aims were to determine whether myenteric ICC (ICC-MY) in human jejunum are pacemaker cells and whether these cells actively propagate pacemaker activity. METHODS: The mucosa and submucosa were removed, and strips of longitudinal muscle were peeled away to reveal the ICC-MY network. ICC networks were loaded with the Ca(2+) indicator fluo-4, and pacemaker activity was recorded via high-speed video imaging at 36.5 degrees C +/- 0.5 degrees C. RESULTS: Rhythmic, biphasic Ca(2+) transients (6.03 +/- 0.33 cycles/min) occurred in Kit-positive ICC-MY. These consisted of a rapidly propagating upstroke phase that initiated a sustained plateau phase, which was associated with Ca(2+) spikes in neighboring smooth muscle. Pacemaker activity was dependent on inositol 1,4,5-triphosphate receptor-operated stores and mitochondrial function. The upstroke phase of Ca(2+) transients in ICC-MY appeared to result from Ca(2+) influx through dihydropyridine-resistant Ca(2+) channels, whereas the plateau phase was attributed to Ca(2+) release from inositol 1,4,5-triphosphate receptor-operated Ca(2+) stores. CONCLUSIONS: Each ICC-MY in human jejunum generates spontaneous pacemaker activity that actively propagates through the ICC network. Loss of these cells could severely disrupt the normal function of the human small intestine.