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      Interstitial Cells of Cajal Are Involved in Neurotransmission in the Gastrointestinal Tract

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          Abstract

          Interstitial cells of Cajal (ICC) are important cells which coordinate gastrointestinal motility. ICC express Kit receptor tyrosine kinase, and Kit immunohistochemistry reveals ICC morphology and distribution in the gastrointestinal musculature. ICC show a highly branched morphology and form unique networks. Myenteric ICC (ICC-MY) are located at the layer of the myenteric plexus and serve as electrical pacemakers. Intramuscular ICC (ICC-IM) and ICC in the deep muscular plexus (ICC-DMP) are distributed within the muscular layers, and are densely innervated by excitatory and inhibitory enteric motor neurons and in close contact with nerve terminals. Recent studies combined with morphological and functional techniques directly revealed that ICC-IM and ICC-DMP are mediators of enteric motor neurotransmission. These types of ICC express several receptors for neurotransmitters such as acetylcholine and substance P and show responses to excitatory nerve stimulations. ICC also express receptive mechanisms for nitric oxide, which is an inhibitory neurotransmitter in the gastrointestinal tract. They can respond to nitrergic nerve stimulation by cyclic GMP production. Kit mutant mice lack ICC-IM and show attenuated postsynaptic responses after intrinsic nerve stimulation. These findings indicate the importance for ICC in neurotransmission in the gastrointestinal tract.

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          A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract.

          Electrical rhythmicity in gastrointestinal muscles has been studied for a century, but the pacemakers driving this phenomenon have been elusive. Anatomic studies suggest that interstitial cells of Cajal (ICC) may be pacemakers and conductors of electrical activity. ICC may also mediate neurotransmission from enteric neurons. Functional evaluations of ICC include the following. (1) Electrophysiology experiments on dissected muscle strips show that slow waves originate from specific sites. These pacemaker areas are populated by networks of ICC that make gap junctions with smooth muscle cells. Removal of pacemaker regions interferes with slow wave generation and propagation. (2) Chemicals that label ICC histochemically can damage ICC and abolish rhythmicity. (3) isolated ICC are spontaneously active, and several voltage-dependent ion channels, including a low-threshold Ca2+ conductance, are expressed. (4) ICC are innervated by enteric neurons, and they respond to neurotransmitters. ICC may produce nitric oxide and amplify inhibitory neurotransmission. (5) Some classes of ICC fall to develop in animals with mutations in c-kit or stem cell factor, the ligand for c-Kit receptors. Without ICC, electrical slow waves are absent. Many questions remain about the function of ICC, but modern technologies should now facilitate rapid progress toward determining the role of these cells in normal physiology and pathological conditions.
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            Interstitial cells of Cajal mediate mechanosensitive responses in the stomach.

            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 microM) and by Ni(2+) (250 microM). Responses to stretch were inhibited by indomethacin (1 microM) 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 W/W(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.
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              Gut pacemaker cells: the interstitial cells of Cajal (ICC).

              This review will focus on the pacemaker mechanisms underlying gastrointestinal autonomic rhythmicity in an attempt to elucidate the differences and similarities between the pacemaker mechanisms in the heart and gut. Interstitial cells of Cajal (ICC) form networks that are widely distributed within the submucosal (ICC-SM), intra-muscular (ICC-IM, ICC-DMP) and inter-muscular layers (ICC-MY) of the gastrointestinal tract from the esophagus to the internal anal sphincter. The ICC generate spontaneously active pacemaker currents that may be recorded as plateau and slow potentials. These pacemaker currents drive the spontaneous electrical and mechanical activities of smooth muscle cells. The enteric nervous system, composed of both the myenteric (inter-muscular) plexus and the submucosal plexus, is also distributed in the gastrointestinal tract from the esophagus to the internal anal sphincter. The role of the ICC and the enteric nervous system in the integrative control of gastrointestinal function and especially of spontaneous rhythmic activity, is still unknown. Nevertheless, at least from the results presented in this review of studies of the jejunum, ileum and proximal colon of the mouse, it is convincing that the ICC drive spontaneous rhythmic motility, although a role for the enteric nervous system in the regulation of spontaneous rhythmic motility cannot be overlooked. Furthermore, intracellular Ca2+ handling has a critical role in the generation of pacemaker activity in the gut and heart, although respective players such as the Ca2+-ATPase of the sarcoplasmic reticulum (endoplasmic reticulum), IP3 receptors, ryanodine receptors and plasma membrane ion channels may have divergent roles in the Ca2+-release refilling cycles. In conclusion, intracellular Ca2+ handling plays a key role in the gut pacemaker responsible for spontaneous rhythmicity, as well as in the cardiac pacemaker responsible for spontaneous beating. Pharmacotherapeutic targeting of intracellular Ca2+ handling mechanisms may be a promising approach to the treatment and cure of gut motility dysfunction.
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                Author and article information

                Journal
                Acta Histochem Cytochem
                AHC
                Acta Histochemica et Cytochemica
                Japan Society of Histochemistry and Cytochemistry (Tokyo, Japan )
                0044-5991
                1347-5800
                28 December 2006
                6 December 2006
                : 39
                : 6
                : 145-153
                Affiliations
                [1 ]Department of Anatomy, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui 910–1193, Japan
                Author notes
                Correspondence to: Satoshi Iino, MD, PhD, Department of Anatomy, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui 910–1193, Japan. E-mail: iinosa@ 123456fmsrsa.fukui-med.ac.jp
                Article
                AHC06023
                10.1267/ahc.06023
                1779949
                17327901
                422665a7-3374-402b-8e54-2758e782f568
                Copyright © 2006 AHC

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 September 2006
                : 18 October 2006
                Categories
                Review

                Clinical chemistry
                neurotransmission,gastrointestinal tract,interstitial cells of cajal,smooth muscle,enteric nervous system

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