| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Topical Review |
1 Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA
 |
Abstract |
|---|
 Top Abstract IntroductionReferences |
|---|
(Received 6 October 2006;
accepted after revision 27 October 2006;
first published online 9 November 2006)
Corresponding author K. M. Sanders: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA. Email: kent{at}unr.edu
|
Introduction |
|---|
|
TopAbstractIntroductionReferences |
|---|
The trend toward the use of genetic models is very evident, and indeed responsible, for most of our progress toward understanding the role of ICC in GI motor function and dysfunction. ICC are a minor component of the tunica muscularis of the gastrointestinal tract (only about 5% of cells present; Ördög et al. 2004); however, these cells have very significant physiological roles in GI motility. At present, we know that ICC generate electrical slow waves which set the basic motor patterns of peristalsis and segmentation in GI organs. ICC form low resistance connections with smooth muscle cells via gap junctions, and slow wave depolarizations conduct into muscle cells. Slow waves are an oscillation of membrane potential that changes the open probability of voltage-dependent Ca2+ channels from a point where there is very little Ca2+ entry via this pathway to a point where Ca2+ entry elicits excitation–contraction coupling. Thus, slow waves organize the contractile activity of GI muscles into a series of phasic contractions. Slow waves are also actively propagated within ICC networks so the spontaneous pacemaker activity of a multitude of ICC can be entrained into a wavefront that is capable of orchestrating contractile patterns such as the spreading ring of contraction in peristalsis or the alternating contractions of segmentation.
The force of intestinal contractions varies from hardly perceptible to powerful concentric contractions that can occlude the lumen of a GI organ. Contractile force is controlled beyond the organization of phasic contractions by slow waves with inputs from the enteric nervous system. Both excitatory and inhibitory motor neurons innervate the musculature and recent studies have shown that both of the dominant motor inputs, i.e. cholinergic and nitrergic, communicate with the smooth muscle cells via ICC that form close synaptic relationships with the nerve terminals of enteric motor neurons. Neural inputs can also influence slow wave frequency, so inputs through ICC can also alter the basic pattern of phasic contractions. ICC have also been linked to stretch-dependent responses in GI muscles, so there also appears to be a sensory role for these cells. This brief review discusses the insights about the role of ICC that have been accomplished using genetic models that, due to loss-of-function mutations, have incomplete development of ICC.
Role of ICC as pacemakers
Several years ago it was noted that the spontaneous electrical depolarizations (slow waves) of GI muscles originate within specific planes in the tunica muscularis. Slow waves were largest in amplitude in specific areas, and when these events were recorded with multiple intracellular electrodes, they always occurred first near the submucosal border of the colon (Smith et al. 1987) or near the region of the myenteric plexus at the border between the circular and longitudinal muscle layers of the stomach and small bowel (Suzuki et al. 1986; Jimenez et al. 1996). These regions are populated by a network of interconnected cells known as interstitial cells of Cajal (ICC), after the neuroanatomist Ramon y Cajal who first described their presence in visceral tissues (Cajal, 1893, 1911). In the myenteric region (ICC-MY) and along the submucosal border of the circular muscle layer (ICC-SM) ICC form an electrical network with many large gap junctions between the processes of adjacent ICC. ICC also form occasional gap junctions with smooth muscle cells, and it was these structures that suggested to anatomists that ICC might be pacemaker cells in the GI tract (cf. Faussone Pellegrini et al. 1977; Thuneberg, 1982). The high density of ICC in regions where slow waves originate greatly strengthened this hypothesis, but definitive tests of this idea were difficult to obtain.
In 1992 a paper appeared suggesting that gastrointestinal pacemaker activity might depend upon signalling through the receptor tyrosine kinase, Kit, because mutations in c-kit led to abnormal contractile patterns in intestinal muscles (Maeda et al. 1992). Examination of intestinal muscles from W mutants (c-kit loss-of-function mutants) or from animals with mutations in the ligand for Kit (stem cell factor, Sl), showed grossly underdeveloped networks of ICC-MY (Ward et al. 1994, 1995; Huizinga et al. 1995). It should be noted that loss of ICC is not complete in the W or Sl mutants examined, and this is because (a) neither W/WV nor Sl/Sld animals carry complete loss-of-function mutations in both alleles or (b) there are other growth factors that can compensate for the loss of Kit signalling in some classes of ICC. ICC are reduced but no class of ICC is entirely lost from the colon, intramuscular ICC that populate the region of the deep muscular plexus (ICC-DMP) are present in the intestine, and ICC-MY are present, but in reduced numbers and distribution in the stomach (Ördög et al. 2002; Hirst et al. 2002b). ICC-MY are largely missing from the small intestine, and ICC-IM are missing from the stomach, lower oesophageal sphincter and pyloric sphincter (Burns et al. 1996; Ward et al. 1998). Similar morphological observations have been made in Ws/Ws (Kit) mutant rats. These animals also lack ICC-MY in the small intestine (Horiguchi & Komuro, 1998; Takeda et al. 2001) and intramuscular ICC (ICC-IM) in the stomach (Ishikawa et al. 1997; Mitsui & Komuro, 2003). Kit mutants or Kit ligand mutants therefore provided an unprecedented opportunity to study the functions of specific classes of ICC in different parts of the GI tract.
Work from Ladd Prosser's laboratory in the 1970s and 1980s predicted that pacemaker activity would originate in the myenteric region of the small intestine (cf. Suzuki et al. 1986). If ICC are the pacemaker cells in the small intestine, then loss of ICC-MY should affect the ability of the small bowel to generate slow wave activity. Recordings from muscles of W/WV intestinal muscles showed complete loss of slow wave activity (Fig. 1; Ward et al. 1994; Huizinga et al. 1995). Similar findings were obtained from muscles of Sl/Sld mice, which would also be expected to have reduced signalling via Kit receptors (Ward et al. 1995). The smooth muscles of these animals are apparently unaffected by Kit or stem cell factor mutations, and the muscles are capable of generating Ca2+ action potentials, contractile responses and responses to agonists (Ward et al. 1994, 2000a; Burns et al. 1996). These data showed the central importance of ICC-MY in generating slow wave activity, and many other models in which ICC-MY have been lost as a result of developmental disruption, postnatal block of Kit receptors, pathophysiological conditions such as obstruction, diabetes, or postsurgical inflammation have confirmed the importance of ICC as pacemaker cells (see Torihashi et al. 1995; Ördög et al. 2000; Chang et al. 2001; Yanagida et al. 2004; Beckett et al. 2006). Simultaneous recordings from ICC-MY and nearby smooth muscle cells have also demonstrated that slow waves occur first in ICC and these events conduct passively to smooth muscle cells (Dickens et al. 1999; Kito & Suzuki, 2003).
|
Role of ICC in neural responses
As stated above, another class of ICC lies intermingled with smooth muscle cells within the muscle bundles of the tunica muscularis throughout the gastrointestinal tract (intramuscular ICC or ICC-IM). ICC-IM form close synaptic contacts with terminals of enteric motor neurons. A role for ICC-IM in neurotransmission was suggested by the anatomical relationship with neurons, but the physiological importance of ICC-IM has been established using animals with mutations in Kit receptors (W/WV; Burns et al. 1996; Ward et al. 2000a; Suzuki et al. 2003) or stem cell factor (Sl/Sld; Beckett et al. 2002).
Macroscopic anatomical relationship between enteric nerve processes and ICC-IM. Morphological studies of several species including humans have shown that varicosities of enteric motor neurons lie in close apposition to ICC-IM (Cajal, 1893, 1911; Taxi, 1952, 1965; Thuneberg, 1989). The close relationship between nerve terminals and ICC-IM was first established by electron microscopy, but the full extent to which the fine intramuscular nerve processes track ICC-IM was not appreciated until it became possible to co-label specific classes of motor neurons and ICC using antibodies for Kit. Double labelling with antibodies against vesicular acetylcholine transporter (vAChT) or neuronal nitric oxide (nNOS) also showed that both excitatory and inhibitory enteric motor neurons are closely associated with ICC-IM and nerve fibres tracked along entire cells and from cell to cell for long distances. ICC-IM also form gap junctions with smooth muscle cells. Thus, electrical signals induced in ICC-IM by neural inputs can conduct to surrounding smooth muscle cells.
Synaptic contacts between enteric motor nerve terminals and ICC-IM. When the contacts between ICC-IM and nerve terminals are carefully examined with electron microscopy, specialized junctions with spacing between cells of less than 20 nm are observed (Daniel & Posey-Daniel, 1984; Wang et al. 1999, 2000; Horiguchi et al. 2003). Such structures may also occur between nerve terminals and smooth muscle cells, but if they exist, they are rare. Spacing between nerve terminals and smooth muscle cells is typically more in the order of at least 100 nm. Ultrastructural studies have identified areas of electron density at junctions between enteric nerve varicosities and ICC-IM in the GI tracts of several species (Roman et al. 1975; Daniel & Posey-Daniel, 1984; Wang et al. 1999, 2000; Mitsui & Komuro, 2002; Horiguchi et al. 2003; Beckett et al. 2005). These junctions are reminiscent of neuronal synapses in the central nervous system (CNS; Sanmarti-Vila et al. 2000; Kennedy, 2000; Aoki et al. 2001) or skeletal neuromuscular junctions (Boaro et al. 1998; Ruegg, 2001). There is little known about the molecular constituents of synaptic specializations in the enteric nervous system; however, members of the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors (SNAREs) that are involved in the release of neurotransmitters are present in developing enteric nerves (Vohra et al. 2006). SNAREs facilitate neurovesicle docking to the presynaptic membrane, fusion of the neurovesicle, and release of neurotransmitter in the synaptic cleft in the CNS and may have a similar role as neurotransmitters released from enteric nerve terminals (Nirasawa et al. 1997; Aguado et al. 1999; Beckett et al. 2005). Several SNARE proteins have been identified in enteric neurons of the murine stomach, including synaptotagmin, syntaxin and SNAP-25 (Beckett et al. 2005). Varicose terminals of cholinergic and nitrergic motor neurons express synaptotagmin and SNAP-25, and these terminals lie in close apposition to ICC-IM, but not to smooth muscle cells (Beckett et al. 2005).
There are also electron-dense regions in ICC-IM opposite the presynaptic membrane specializations at enteric motor nerve terminals. The membrane specializations in ICC-IM are structurally similar to the specializations in postsynaptic cells in the CNS populated by postsynaptic density proteins (PSDs). Transcripts for two postsynaptic density proteins (PSD-93 and PSD-95) were detected by RT-PCR in the gastric fundus and antrum. Both transcripts are reduced in gastric muscles of W/WV mice. Immunohistochemical studies using antibodies directed toward the PDZ domain of the PSD-95 family members, including PSD-95 and PSD-93, and SAP 97, showed that these proteins were expressed by ICC-IM, but labelling was not resolved in smooth muscle cells (Beckett et al. 2005). These observations demonstrate that enteric motor neurons form synaptic specializations with ICC-IM and suggest that motor neurons innervate ICC-IM. In contrast smooth muscle cells may receive little or no direct innervation from motor neurons. It was a novel idea that synaptic specializations are necessary for neurotransmission in visceral smooth muscles.
Functional involvement of ICC-IM in motor neurotransmission. The importance of ICC-IM in enteric motor neurotransmission was demonstrated in physiological studies that compared neural responses in gastric muscles of wild-type animals with muscles of W/WV and Sl/Sld mice lacking ICC-IM (Burns et al. 1996; Ward et al. 2000a). Cholinergic excitatory and nitrergic inhibitory junction potentials are greatly reduced in amplitude in fundus muscles lacking ICC-IM (Fig. 2). Muscles of mutant animals have no reduction in varicose cholinergic or nitrergic nerve processes within the musculature, no reduction in the release of transmitter upon nerve stimulation, no loss of postjunctional responses to exogenous transmitter, and no loss of nerve cell bodies in the myenteric plexus or nerve fibres in the circular muscle layer (Burns et al. 1996; Beckett et al. 2002). Long-term stimulation of muscles does not appear to recruit direct smooth muscle responses by build-up and overflow of transmitters from ICC-IM to smooth muscle receptors. Mechanical studies showed essentially no cholinergic or nitrergic responses with 30 s of stimulation at up to 10 Hz (Beckett et al. 2002). Inhibition of acetylcholine breakdown, however, revealed slowly developing junctional potentials that were retained in mutant muscles lacking ICC-IM. These responses were interpreted to be due to transmitter overflow to smooth muscle muscarinic receptors when transmitter breakdown was blocked. Thus, it appears that ICC-IM are the cells that are innervated by cholinergic and nitrergic motor neurons, and the transmitters released by these neurons are confined to the synaptic structures between neurons and ICC-IM. It appears that ACh and NO are normally inactivated by metabolic breakdown or diffusional dilution before they can bind to smooth muscle receptors.
|
It is unclear at present whether the inhibitory responses to nitrergic nerve stimulation are mediated entirely by electrical responses transmitted from ICC-IM to smooth muscle cells. Some studies suggest that NO released from nerves induces inhibition of contractions that are disassociated with changes in membrane potential or intracellular Ca2+ (e.g. Bayguinov & Sanders, 1998; Dickens et al. 2000). These observations suggest that changes in Ca2+ sensitivity of the contractile apparatus may be important in nitrergic motor responses (Nishimura & van Breemen, 1989). Such a mechanism might require a paracrine role for ICC-IM where, in addition to electrical effects, NO stimulates production of an inhibitory mediator by ICC-IM that diffuses to nearby smooth muscle cells and affects the contractile activity via pharmaco-mechanical coupling (Somlyo & Somlyo, 1994).
Another indication of the role of ICC-IM in neural responses comes from an analysis of the chronotropic effects of cholinergic nerve stimulation in the distal stomach. In this region dominant, intrinsic pacemaker activity comes from ICC-MY (as discussed above). The frequency of antral muscles can be driven to much higher levels than the spontaneous, intrinsic frequency by electrical pacing (Kelly & La Force, 1972; Sarna & Daniel, 1973; McCallum, 1987; Miedema et al. 1992; Hirst et al. 2002a), and it is possible to pace the stomach with short duration pulses of electric field stimulation (EFS) by activation of intrinsic motor neurons (Fig. 3). Pacing with short pulses is blocked by tetrodotoxin and atropine, suggesting the effect is mediated by cholinergic neurons (Beckett et al. 2003). The simplest design for neural control of pacemaker activity would be to innervate the dominant pacemaker cells in the myenteric region. However, ICC-MY, while close to the interganglionic processes of neurons within the myenteric plexus, do not form the close associations with nerve terminals as seen with ICC-IM. EFS of antral muscles from W/WV mice, which possess ICC-MY, but have no ICC-IM (Burns et al. 1996; Ördög et al. 2002; Hirst et al. 2002b) failed to phase advance, pace, or even increase the basal frequency of slow wave activity (Beckett et al. 2003; Forrest et al. 2006). These observations show that ICC-IM are exclusively innervated and neural inputs are not conveyed by connectivity or overflow of acetylcholine onto ICC-MY. It should be noted that with longer stimulation pulses (e.g. 1.0–2.0 ms), EFS phase advanced and entrained slow waves in wild-type and W/WV animals. Pacing with 1–2 ms pulses was not inhibited by TTX or atropine, suggesting that this form of stimulation directly activated the pacemaker mechanism in ICC-MY (Fig. 3; Beckett et al. 2003).
|
Cellular mechanisms in ICC-IM driven by cholinergic stimulation
Unitary potentials are generated in ICC-IM by Ca2+ release from inositol 1,4,5-trisphosphate (IP3) receptor-operated stores (Suzuki & Hirst, 1999; Van Helden et al. 2000; Ward et al. 2000b). Stimulation of cholinergic nerves and activation of postjunctional M3 receptors (expressed in ICC-IM; Epperson et al. 2000) would be expected to activate phospholipase C
and enhance production of IP3. Raising IP3 levels would promote IP3 receptor-operated Ca2+ release from intracellular stores and phase advance pacemaker activity. In support of this model is the observation that excitatory junction potentials are absent in the gastric fundus of mutant animals lacking M3 receptors (S. M. Ward & K. M. Sanders, unpublished observation).
The mechanism of pacing of slow waves by direct stimulation of ICC-MY in wild-type and W/WV mice is more controversial. Some investigators have suggested that injection of current activates slow waves through voltage-dependent enhancement of IP3 synthesis (e.g. van Helden et al. 2000), perhaps due to a voltage sensor linked to phospholipase (PLC) (Mahaut-Smith et al. 1999). Although voltage-dependent synthesis of IP3 has been reported in response to long duration depolarization pulses (Mahaut-Smith et al. 1999), this phenomenon has never been shown to occur in ICC. Others believe that direct electrical pacing occurs due to activation of a voltage-dependent Ca2+ conductance (Kim YC et al. 2002). ICC express dihydropyridine-resistant Ca2+ channels (low-voltage-activated) (Lee & Sanders, 1993; Kim YC et al. 2002), and these channels permit Ca2+ entry that could enhance the open probability of IP3 receptors and phase advance slow waves. There is a time delay between depolarization stimuli and the activation of slow waves, and this seems to favour a multistep process coupling depolarization to the initiation of pacemaker currents (Hirst et al. 2002c).
Role of ICC-IM in the innervation of GI tissues by afferent nerves. Anterograde tracing experiments following injections of the nodose ganglia with germ agglutinin–horseradish peroxidase or with the fluorescent carbocyanine dye DiI have revealed the locations of vagal afferent nerve fibres within different regions of the GI tract. In the stomach vagal afferents terminate in the intermuscular region around myenteric ganglia as interganglionic laminar endings (IGLEs) and these endings have been shown to respond to stretch (Zagorodnyuk et al. 2001). Vagal afferents also terminate within the gastric muscle layers as intramuscular arrays (IMAs). W/WV and Sl/Sld mutants, that lack ICC-IM, have significantly reduced numbers of intramuscular arrays in their forestomachs compared to muscles of wild-type controls (Fox et al. 2001, 2002). IMAs terminate outside the muscle wall and do not seem to find their final targets, suggesting that ICC-IM might secrete a neurotrophic factor that allows for the growth and proper homing of this population of afferent terminals in the stomach wall. It is currently not known whether ICC-IM are important for the survival of these afferents once they are established in the gastric wall. Recent experiments examining the responses of afferent fibre units in response to stretch have shown that there is a loss of mechanosensitive units in W/WV mice that are responsive to moderate stretch of the stomach wall. These changes cannot be explained by the alteration in gastric compliance that occurs in W/WV mice due to the loss of ICC-IM. The reduction of IMAs from the gastric wall of W/WV mice and the loss of a mechanosensitive unit would suggest that IMAs provide sensory input to the CNS during moderate stretch of the stomach wall (Beyak et al. 2006).
Stretch-dependent responses of gastric muscles mediated by ICC-IM
Some anatomists have suggested that ICC might also have a role as stretch receptors in the GI muscles (Thuneberg, 1989). GI organs undergo considerable changes in size from the interdigestive period to the digestive state. Motor responses to changes in organ volume have largely been attributed to neural responses through local and vagal reflexes that facilitate, for example, gastric accommodation and increased peristaltic contractions in the distal stomach (Cannon, 1911; Paton & Vane, 1963; Hennig et al. 1997).
The role of ICC in stretch-dependent responses in the gastric antrum has recently been investigated by using tissues isolated from wild-type and W/WV mice (Won et al. 2005). Antral muscles, isolated from wild-type animals display membrane depolarization and a marked increase in pacemaker frequency in response to relatively small increases in muscle length. This change in activity may have been missed by many investigators as it is apparent only during the active change in length and accommodates upon sustained stretch, and is reversible when muscles are returned to resting length. This response to stretch is not dependent upon neuronal reflexes or on the tone of the muscle as TTX and the L-type calcium channel antagonist nifedipine have no effect on these responses (Won et al. 2005). The response to stretch is absent in muscles of W/WV mice, suggesting that ICC-IM provide stretch sensitivity in gastric muscles (Fig. 4). Stretch-dependent responses in the antrum are inhibited by indomethacin, suggesting involvement of cyclooxygenase enzymes and production of a prostanoid in this response. The effects of stretch on antral muscles are mimicked by the prostaglandin E receptor suptype (EP3) agonists sulprostone and ONO-AE-248, suggesting that EP3 receptors might mediate stretch-dependent responses in ICC-IM (Kim et al. 2002). ICC-IM express COX-II (Porcher et al. 2002), and the stretch response is also missing in COX-II knock-out mice (Won et al. 2005). Stretch may be transduced in ICC-IM by activation of phospholipase A2 and liberation of arachidonic acid; however, this hypothesis has not been fully investigated.
|
|
References |
|---|
|
TopAbstractIntroductionReferences |
|---|
Aoki C, Miko I, Oviedo H, Mikeladze-Dvali T, Alexandre L, Sweeney N & Bredt DS (2001). Electron microscopic immunocytochemical detection of PSD-95, PSD-93, SAP-102, and SAP-97 at postsynaptic, presynaptic, and nonsynaptic sites of adult and neonatal rat visual cortex. Synapse 40, 239–257.[CrossRef][Medline]
Bayguinov O & Sanders KM (1998). Dissociation between electrical and mechanical responses to nitrergic stimulation in the canine gastric fundus. J Physiol 509, 437–448.
Beckett EAH, Horiguchi K, Khoyi M, Sanders KM & Ward SM (2002). Loss of enteric motor neurotransmission in the gastric fundus of Sl/Sld mice. J Physiol 543, 871–887.
Beckett EAH, McGeough CA, Sanders KM & Ward SM (2003). Pacing of interstitial cells of Cajal in the murine gastric antrum: neurally mediated and direct stimulation. J Physiol 553, 545–559.
Beckett EAH, Ro S, Bayguinov Y, Sanders KM & Ward SM (2006). Kit signaling is essential for development and maintenance of interstitial cells of Cajal and electrical rhythmicity in the embryonic gastrointestinal tract. Dev Dyn; DOI: 10.1002/dvdy.20929.
Beckett EAH, Takeda Y, Yanase H, Sanders KM & Ward SM (2005). Synaptic specializations exist between enteric motor nerves and interstitial cells of Cajal in the murine stomach. J Comp Neurol 493, 193–206.[CrossRef][Medline]
Beyak M, Ward SM & Grundy D (2006). Sub-population specific deficits of vagal gastric mechanosensitivity in c-kit deficient W/WV mutant mice. Gastroenterology 130, 242.
Boaro SN, Soares JC & Konig B (1998). Comparative structural analysis of neuromuscular junctions in mice at different ages. Anat Anz 180, 173–179.[Medline]
Burns AJ, Lomax AE, Torihashi S, Sanders KM & Ward SM (1996). Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach. Proc Natl Acad Sci U S A 93, 12008–12013.
Cajal SR (1893). Sur les ganglions et plexus nerveux de l'intestin. C R Soc Biol (Paris) 45, 217–223.
Cajal SR (1911). Histologie du système nerveux de l'homme et des vertébrés, vol. 2, pp. 891–942. Maloine, Paris.
Cannon WB (1911). The Mechanical Factors of Digestion, ed. Hill L & Bullock W, pp. 48–58. Longmans Green, New York.
Chang I-Y, Glasgow NJ, Takayama I, Horiguchi K, Sanders KM & Ward SM (2001). Loss of interstitial cells of Cajal and development of electrical dysfunction in small bowel obstruction. J Physiol 536, 555–568.
Daniel EE & Posey-Daniel V (1984). Neuromuscular structures in opossum esophagus: role of interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol 246, G305–G315.
Dickens EJ, Edwards FR & Hirst GD (2000). Vagal inhibition in the antral region of guinea pig stomach. Am J Physiol Gastrointest Liver Physiol 279, G388–G399.
Dickens EJ, Hirst GD & Tomita T (1999). Identification of rhythmically active cells in guinea-pig stomach. J Physiol 514, 515–531.
DiMarino AJ & Cohen S (1973). The adrenergic control of lower esophageal sphincter function. An experimental model of denervation supersensitivity. J Clin Invest 52, 2264–2271.[Medline]
Edwards FR, Hirst GD & Suzuki H (1999). Unitary nature of regenerative potentials recorded from circular smooth muscle of guinea-pig antrum. J Physiol 519, 235–250.
Epperson A, Halton WJ, Callaghan B, Doherty P, Walker RL, Sanders KM, Ward SM & Horwitz B (2000). Molecular markers expressed in cultured and freshly isolated interstitial cells of cajal. Am J Physiol 279, C529–C539.
Faussone Pellegrini MS, Cortesini C & Romagnoli P (1977). Ultrastructure of the tunica muscularis of the cardial portion of the human esophagus and stomach, with special reference to the so-called Cajal's interstitial cells. Arch Ital Anat Embriol 82, 157–177.[Medline]
Forrest AS, Ördög T & Sanders KM (2006). Neural regulation of slow-wave frequency in the murine gastric antrum. Am J Physiol Gastrointest Liver Physiol 290, G486–G495.
Fox EA, Phillips RJ, Byerly MS, Baronowsky EA, Chi MM & Powley TL (2002). Selective loss of vagal intramuscular mechanoreceptors in mice mutant for steel factor, the c-Kit receptor ligand. Anat Embryol 205, 325–342.[CrossRef][Medline]
Fox EA, Phillips RJ, Martinson FA, Baronowsky EA & Powley TL (2001). C-Kit mutant mice have a selective loss of vagal intramuscular mechanoreceptors in the forestomach. Anat Embryol 204, 11–26.[CrossRef][Medline]
Hashitani H, Garcia-Londono AP, Hirst GD & Edwards FR (2005). Atypical slow waves generated in gastric corpus provide dominant pacemaker activity in guinea pig stomach. J Physiol 569, 459–465.
Hennig GW, Brookes SJ & Costa M (1997). Excitatory and inhibitory motor reflexes in the isolated guinea-pig stomach. J Physiol 501, 197–212.
Hirst GD, Beckett EA, Sanders KM & Ward SM (2002b). Regional variation in contribution of myenteric and intramuscular interstitial cells of Cajal to generation of slow waves in mouse gastric antrum. J Physiol 540, 1003–1012.
Hirst GD, Bramich NJ, Teramoto N, Suzuki H & Edwards FR (2002c). Regenerative component of slow waves in the guinea-pig gastric antrum involves a delayed increase in [Ca2+]i and Cl– channels. J Physiol 540, 907–919.
Hirst GD, Dickens EJ & Edwards FR (2002a). Pacemaker shift in the gastric antrum of guinea-pigs produced by excitatory vagal stimulation involves intramuscular interstitial cells. J Physiol 541, 917–928.
Horiguchi K & Komuro T (1998). Ultrastructural characterization of interstitial cells of Cajal in the rat small intestine using control and Ws/Ws mutant rats. Cell Tissue Res 293, 277–284.[CrossRef][Medline]
Horiguchi K, Sanders KM & Ward SM (2003). Enteric motor neurons form synaptic-like junctions with interstitial cells of Cajal in the canine gastric antrum. Cell Tissue Res 311, 299–313.[Medline]
Horiguchi K, Semple GS, Sanders KM & Ward SM (2001). Distribution of pacemaker function through the tunica muscularis of the canine gastric antrum. J Physiol 537, 237–250.
Huizinga JD, Thuneberg L, Kluppel M, Malysz J, Mikkelsen HB & Bernstein A (1995). W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 373, 347–349.
Ishikawa K, Komuro T, Hirota S & Kitamura Y (1997). Ultrastructural identification of the c-kit-expressing interstitial cells in the rat stomach: a comparison of control and Ws/Ws mutant rats. Cell Tissue Res 289, 137–143.[CrossRef][Medline]
Jimenez M, Cayabyab FS, Vergara P & Daniel EE (1996). Heterogeneity in electrical activity of the canine ileal circular muscle: interaction of two pacemakers. Neurogastroenterol Motil 8, 339–349.[Medline]
Kelly KA & La Force RC (1972). Pacing the canine stomach with electric stimulation. Am J Physiol 222, 588–594.
Kennedy MB (2000). Signal-processing machines at the postsynaptic density. Science 290, 750–754.
Kim TW, Beckett EA, Hanna R, Koh SD, Ördog T, Ward SM & Sanders KM (2002). Regulation of pacemaker frequency in the murine gastric antrum. J Physiol 538, 145–157.
Kim YC, Koh SD & Sanders KM (2002). Voltage-dependent inward currents of interstitial cells of Cajal from murine colon and small intestine. J Physiol 541, 797–810.
Kito Y, Fukuta H, Yamamoto Y & Suzuki H (2002). Excitation of smooth muscles isolated from the guinea-pig gastric antrum in response to depolarization. J Physiol 543, 155–167.
Kito Y & Suzuki H (2003). Properties of pacemaker potentials recorded from myenteric interstitial cells of Cajal distributed in the mouse small intestine. J Physiol 553, 803–818.
Lee HK & Sanders KM (1993). Comparison of ionic currents from interstitial cells and smooth muscle cells of canine colon. J Physiol 460, 135–152.
McCallum RW (1987). Gastric emptying disorders. Tests and treatments. Postgrad Med 81, 67–76.[CrossRef][Medline]
Maeda H, Yamagata A, Nishikawa S, Yoshinaga K, Kobayashi S, Nishi K & Nishikawa S (1992). Requirement of c-kit for development of intestinal pacemaker system. Development 116, 369–375.[Medline]
Mahaut-Smith MP, Hussain JF & Mason MJ (1999). Depolarization-evoked Ca2+ release in a non-excitable cell, the rat megakaryocyte. J Physiol 515, 385–390.
Miedema BW, Sarr MG & Kelly KA (1992). Pacing the human stomach. Surgery 111, 143–150.[Medline]
Mitsui R & Komuro T (2002). Direct and indirect innervation of smooth muscle cells of rat stomach, with special reference to the interstitial cells of Cajal. Cell Tissue Res 309, 219–227.[CrossRef][Medline]
Mitsui R & Komuro T (2003). Distribution and ultrastructure of interstitial cells of Cajal in the gastric antrum of wild-type and Ws/Ws rats. Anat Embryol (Berl) 206, 453–460.[Medline]
Nirasawa Y, Ito Y, Seki N & Akagawa K (1997). HPC-1/syntaxin-1A activity in the enteric nervous system of developing rat gastrointestinal tract. J Smooth Muscle Res 33, 61–66.[Medline]
Nishimura J & van Breemen C (1989). Direct regulation of smooth muscle contractile elements by second messengers. Biochem Biophys Res Com 163, 929–935.[CrossRef][Medline]
Ördög T, Baldo M, Danko R & Sanders KM (2002). Plasticity of electrical pacemaking by interstitial cells of Cajal and gastric dysrhythmias in W/W mutant mice. Gastroenterology 123, 2028–2040.[CrossRef][Medline]
Ördög T, Redelman D, Horvath VJ, Miller LJ, Horowitz B & Sanders KM (2004). Quantitative analysis by flow cytometry of interstitial cells of Cajal, pacemakers, and mediators of neurotransmission in the gastrointestinal tract. Cytometry A 62, 139–149.[CrossRef][Medline]
Ördög T, Takayama I, Cheung WKT, Ward SM & Sanders KM (2000). Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis. Diabetes 49, 1731–1739.[Abstract]
Paton WDM & Vane JR (1963). Analysis of the responses of the isolated stomach to electrical stimulation and to drugs. J Physiol 165, 10–46.
Porcher C, Horowitz B, Bayguinov O, Ward SM & Sanders KM (2002). Constitutive expression and function of cyclooxygenase-2 in murine gastric muscles. Gastroenterology 122, 1442–1454.[CrossRef][Medline]
Roman C, Gonella J, Niel JP, Condamin M & Miolan JP (1975). Effets de la stimulation vagale et de l'adrenaline sur la musculeuse lisse du bas oesophage du chat. INSERM 50, 415–422.
Ruegg MA (2001). Molecules involved in the formation of synaptic connections in muscle and brain. Matrix Biol 20, 3–12.[CrossRef][Medline]
Sanmarti-Vila L, tom Dieck S, Richter K, Altrock W, Zhang L, Volknandt W, Zimmermann H, Garner CC, Gundelfinger ED & Dresbach T (2000). Membrane association of presynaptic cytomatrix protein bassoon. Biochem Biophys Res Commun 275, 43–46.[CrossRef][Medline]
Sarna SK & Daniel EE (1973). Electrical stimulation of gastric electrical control activity. Am J Physiol 225, 125–131.
Sergeant GP, Large RJ, Beckett EA, McGeough CM, Ward SM & Horowitz B (2002). Microarray comparison of normal and W/WV mice in the gastric fundus indicates a supersensitive phenotype. Physiol Genomics 11, 1–9.
Smith TK, Reed JB & Sanders KM (1987). Interaction of two electrical pacemakers in muscularis of canine proximal colon. Am J Physiol Cell Physiol 252, C290–C299.
Somlyo AP & Somlyo AV (1994). Signal transduction and regulation in smooth muscle. Nature 372, 231–236.
Suzuki H & Hirst GD (1999). Regenerative potentials evoked in circular smooth muscle of the antral region of guinea-pig stomach. J Physiol 517, 563–573.
Suzuki N, Prosser CL & Dahms V (1986). Boundary cells between longitudinal and circular layers: essential for electrical slow waves in cat intestine. Am J Physiol Gastrointest Liver Physiol 250, G287–G294.
Suzuki H, Ward SM, Bayguinov YR, Edwards FR & Hirst GD (2003). Involvement of intramuscular interstitial cells in nitrergic inhibition in the mouse gastric antrum. J Physiol 546, 751–763.
Takeda M, Takayama I, Terada N, Baba T, Ward SM, Ohno S & Fujino MA (2001). Immunoelectron-microscopic study of Kit-expressing cells in the jejunum of wildtype and Ws/Ws rats. Cell Tissue Res 304, 21–30.[CrossRef][Medline]
Taxi J (1952). Cellules de Schwann et ‘cellules interstitielles de Cajal’ au niveau des plexus nerveux de la musculeuse intestinale du Cobaye: retour aux definitions. Arch Anat Microsc Morph Exp 41, 281–304.
Taxi J (1965). Contribution á l'étude des connexions des neurones moteurs du systeme nerveux sutonome. Ann Sci Nat Zool Biol Anim 7, 413–674.
Thuneberg L (1982). Interstitial cells of Cajal: intestinal pacemaker cells? Adv Anat Embryol Cell Biol 71, 1–130.[Medline]
Thuneberg L (1989). Interstitial cells of Cajal. In Handbook of Physiology: The Gastrointestinal System, ed. Wood JD, vol. 1. pp. 349–386. American Physiological Society, Bethesda, MD, USA.
Torihashi S, Ward SM, Nishikawa S, Nishi K, Kobayashi S & Sanders KM (1995). c-Kit-dependent development of interstitial cells and electrical activity in the murine gastrointestinal tract. Cell Tissue Res 280, 97–111.[Medline]
van Helden DF, Imtiaz MS, Nurgaliyeva K, von der Weid P & Dosen PJ (2000). Role of calcium stores and membrane voltage in the generation of slow wave action potentials in guinea-pig gastric pylorus. J Physiol 524, 245–265.
Vohra BP, Tsuji K, Nagashimada M, Uesaka T, Wind D, Fu M, Armon J, Enomoto H & Heuckeroth RO (2006). Differential gene expression and functional analysis implicate novel mechanisms in enteric nervous system precursor migration and neuritogenesis. Dev Biol 298, 259–271.[CrossRef][Medline]
Wang XY, Sanders KM & Ward SM (1999). Intimate relationship between interstitial cells of Cajal and enteric nerves in the guinea-pig small intestine. Cell Tissue Res 295, 247–256.[CrossRef][Medline]
Wang XY, Sanders KM & Ward SM (2000). Relationship between interstitial cells of Cajal and enteric motor neurons in the murine proximal colon. Cell Tissue Res 302, 331–342.[CrossRef][Medline]
Ward SM, Beckett EA, Wang X, Baker F, Khoyi M & Sanders KM (2000a). Interstitial cells of Cajal mediate cholinergic neurotransmission from enteric motor neurons. J Neurosci 20, 1393–1403.
Ward SM, Burns AJ, Torihashi S, Harney SC & Sanders KM (1995). Impaired development of interstitial cells and intestinal electrical rhythmicity in steel mutants. Am J Physiol Cell Physiology 269, C1577–C1585.
Ward SM, Burns AJ, Torihashi S & Sanders KM (1994). Mutation of the proto-oncogene c-kit blocks development of interstitial cells and electrical rhythmicity in murine intestine. J Physiol 480, 91–97.
Ward SM, Morris G, Reese L, Wang XY & Sanders KM (1998). Interstitial cells of Cajal mediate enteric inhibitory neurotransmission in the lower esophageal and pyloric sphincters. Gastroenterology 115, 314–329.[CrossRef][Medline]
Ward SM, Ördög T, Koh SD, Baker SA, Jun JY, Amberg G, Monaghan K & Sanders KM (2000b). Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria. J Physiol 525, 355–361.
Won KJ, Sanders KM & Ward SM (2005). Interstitial cells of Cajal mediate mechanosensitive responses in the stomach. Proc Natl Acad Sci U S A 102, 14913–14918.
Yanagida H, Yanase H, Sanders KM & Ward SM (2004). Intestinal surgical resection disrupts electrical rhythmicity, neural responses, and interstitial cell networks. Gastroenterology 127, 1748–1759.[CrossRef][Medline]
Zagorodnyuk VP, Chen BN & Brookes SJ (2001). Intraganglionic laminar endings are mechano-transduction sites of vagal tension receptors in the guinea-pig stomach. J Physiol 534, 255–268.
|
Acknowledgements |
|---|
This article has been cited by other articles:
|
|
 |
|
  S. Allix, E. Reyes-Gomez, G. Aubin-Houzelstein, D. Noel, L. Tiret, J.-J. Panthier, and F. Bernex Uterine Contractions Depend on KIT-Positive Interstitial Cells in the Mouse: Genetic and Pharmacological Evidence Biol Reprod, September 1, 2008; 79(3): 510 - 517. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. I. Kotlikoff From genotype to phenotype and back J. Physiol., January 1, 2007; 578(1): 7 - 8. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
