THEME
Physiology and Pathophysiology of the Interstitial Cell of Cajal: From Bench to Bedside
II. Gastric motility: lessons from
mutant mice on slow waves and innervation
Jan D.
Huizinga
McMaster University, Hamilton L8N 3Z5, Ontario, Canada
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ABSTRACT |
The stomach harbors a network of
interstitial cells of Cajal (ICC) associated with Auerbach's plexus as
well as intramuscular ICC within the muscle layers that make close
apposition contact with nerve varicosities. ICC are critical for
slow-wave generation, making ICC the pacemaker cells of the gut,
allowing rhythmic peristaltic motor patterns in the mid- and distal
stomach. ICC also play a role in neurotransmission, but its importance
relative to direct muscle innervation is still under investigation. The
role of ICC in many control functions of gastric motility in humans
needs further examination. The pathophysiology of ICC in disease can be
partially assessed by immunohistochemistry and electron microscopy on
tissue samples. Electrogastrogram measurements may also play a
role, but this technique needs further refinement. Communication between ICC and muscle may involve electrical coupling, metabolic coupling through gap junctions, or secretion of nitric oxide or carbon monoxide.
interstitial cells of Cajal; stomach; gastric emptying; innervation; distension
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INTRODUCTION |
GASTRIC MOTILITY
INVOLVES complex processes in which parts of the stomach relax to
accept food from the esophagus, whereas other parts deliver chyme to
the small bowel at a rate optimal for digestion and absorption. Before
delivery to the small intestine, the stomach stores, mixes, grinds, and
sorts food substances into liquid and solid components that are
processed and cleared by different mechanisms. Both disease and surgery
may cause disruption of any of these complex functions, leading to a
variety of clinical disorders including delayed gastric emptying,
postgastrectomy syndromes, and gastric atony. To understand the
physiological basis for these alterations, a more detailed knowledge of
the mechanisms underlying control of gastric motility is essential. Smooth muscle and enteric nerves together with interstitial cells of
Cajal (ICC) form complex control systems. This review attempts to put
recent work on ICC related to stomach motor physiology into context.
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GENERAL INTRODUCTION TO ICC |
There are two distinct classes of ICC in the stomach of humans and
animal models (Fig. 1). The first type of
ICC is spindle shaped and scattered throughout the circular and
longitudinal muscle layers from the fundus into the distal antrum.
These ICC are closely associated with both excitatory and inhibitory
nerve fibers and identified as intramuscular ICC (ICC-IM).
Functionally, they may serve as mediators interposing between enteric
nerves and smooth muscle cells. In addition, they may serve to modify slow-wave activity. The second type of ICC is triangular or irregularly shaped with multiple processes forming highly branching networks in
between the longitudinal and circular muscle layers of the corpus and
antrum but not the fundus. The known function of these ICC is their
role in pacemaker generation. These ICC are associated with Auerbach's
plexus (ICC-AP). Because Auerbach's plexus is often called myenteric
plexus, ICC-AP are also referred to as ICC-MY or IC-MY, although the
term myenteric plexus really refers to all intrinsic neural structures
within the musculature (34).

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Fig. 1.
Different classes of interstitial cells of Cajal (ICC) in the
stomach muscle wall. A: multipolar ICC with triangular or
stellate-shaped cell bodies comprise a network of ICC associated with
the ganglia and nerves of Auerbach's plexus. This network is found in
the corpus antrum region but not in the fundus. B:
spindle-shaped ICC that are found throughout the circular and
longitudinal muscle and are closely connected to enteric nerve
varicosities. Pictures generated by Dr. X.-Y. Wang. Confocal microscopy
of ICC in the mouse antrum (A) and fundus (B),
stained using c-Kit antibodies.
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ICC AND INNERVATION |
The evidence that ICC-IM play a role in neurotransmission has been
reviewed recently (40, 43). In the stomach, ICC-IM form
close (~25 nm) contacts with enteric nerves that have nitric oxide
(NO), acetylcholine, or substance P as their primary neurotransmitter (2, 41). W/Wv mutant mice have abnormal Kit protein that results in underdevelopment of certain classes of ICC, and these mice
lack ICC-IM in the stomach and lower esophageal sphincter (LES). Ward and co-workers (2, 43) showed that the
stomach of W/Wv mice has reduced NO-dependent postjunctional responses and suggested a critical role for ICC-IM in inhibitory
innervation. However, Sivarao and co-workers (28)
found normal LES relaxation in vivo in W/Wv mice, and they suggest that
ICC-IM may not be essential for NO-mediated inhibitory innervation. The
role of NO in the inhibitory innervation was demonstrated by lack of
inhibition in neuronal NO synthase knockout mice
(28). ICC-IM are also proposed to play a role in
cholinergic excitatory responses in the fundus (41).
Because smooth muscle cells are rich in muscarinic receptors and
because neurotransmittor is released within the musculature on
stimulation, direct cholinergic muscle innervation will occur as well.
It is therefore to be investigated in which cholinergically mediated
motor control functions ICC-IM play a complementary or exclusive
role. All ICC are richly innervated with numerous
close-apposition contacts. The conventional wisdom is that smooth
muscle cells do not establish close contacts with nerves, the
implication being that neurotransmitters have to travel a relatively
large distance to reach smooth muscle receptors. Although many nerve
varicosities do not appear to have close contact with muscle cells,
close contacts do occur with membrane gaps as narrow as 20 nm without
the basal lamina (11). Faussone-Pellegrini described such
contacts in the human stomach, including protrusions from varicosities
fitting into grooves in smooth muscle cells (Fig.
2) (10, 11).
Close-apposition contacts between nerves and smooth muscle
cells also occur in the mouse and rat stomach (M. S. Faussone-Pellegrini, personal communication). Nevertheless, the
innervation of ICC is much more dense, with ICC often wedged between
nerve and muscle. It is therefore likely that ICC-IM play an important
complementary role in neurotransmission. It is also possible that
ICC-IM are intermediaries for unique functional neural pathways yet to
be characterized. It should not be forgotten in studies that use mutant
mice with loss of ICC-IM that the mutation itself, or the loss of ICC
specifically, may directly affect smooth muscle cells (see below).

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Fig. 2.
Close apposition contacts between ICC and muscle cells
with nerves A: human stomach, corpus. A protrusion from a
nerve varicosity fits perfectly into a groove formed by a smooth muscle
cell. B: human stomach, lesser curvature. Two nerve endings,
one close, the other near the same smooth muscle cell. C:
human stomach within the circular muscle layer of the corpus. Nerve
endings (*) are engulfed by ICC [stomach ICC (S-ICC)] making long
close-apposition contact. Original figures (A and
B) provided by Faussone-Pellegrini are simular to Figs. 28 and 29 from Ref. 11. C is adopted from Fig. 18 in Ref. 10.
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A possible mechanism of communication between nerve and ICC and muscle
is that neural activity initiates electrical and/or biochemical events
in ICC that are transmitted to smooth muscle cells through gap
junctions. However, not all ICC that are proposed to have a function in
muscle innervation are coupled to smooth muscle cells by gap junctions;
hence alternative mechanisms have to be considered (5). In
addition, it is likely that products synthesized by ICC, such as NO and
carbonmonoxide, will reach smooth muscle cells and influence their
excitability (8, 27).
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ICC AND SLOW-WAVE GENERATION |
ICC-AP are essential for the generation of slow-wave activity.
Bauer showed that slow-wave activity originated in the Auerbach's plexus region, where the ICC-AP are located (1).
Simultaneous recording from ICC and smooth muscle cells in the guinea
pig stomach showed that ICC generated "driving potentials" that
were complemented by smooth muscle cells to produce complete slow waves
(Fig. 3) (6). The frequency
and propagation characteristics of the peristaltic contractions of the
mid- and distal stomach are controlled by the slow waves. Excitation
through distension and/or enteric neural activity generates smooth
muscle action potentials that occur confined to the most depolarized
phase of the slow waves. Because of this, the maximum frequency of the
peristaltic contractions is the same as the frequency of the slow
waves. Hence, whereas the enteric nerves are essential to evoke
excitation, in the corpus-antrum it is not bolus-induced peristaltic
reflexes that control propagation. The force of the contractions is
determined by the degree of action potential generation on the plateau
phase of the slow wave and changes in the plateau phase itself. This is
determined by the level of excitation of the musculature, hence the
level of distension and neural and hormonal input. Lammers and
co-workers (17) showed the relationships between slow
waves and action potentials. Figure 4
shows the action potentials occurring as "patches" associated with
the slow-wave activity. The slow wave causes an area of depolarization, its extent determined by the length of the plateau phase. Within this
area of depolarization, action potentials can be evoked that can
propagate in several directions and for various lengths of time,
depending on the degree of stimulation. The degree of stimulation determines how much of the slow wave is above threshold for the generation of action potentials and whether the slow-wave duration is
increased. The overall contraction strength will be, in large part,
determined by the extent of action potential generation. At the organ
level, the propagation of the contraction wave will follow the aborally
propagating slow wave.

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Fig. 3.
Spontaneous activity recorded from ICC within tissue
reveals high-amplitude slow waves with very fast rate of rise.
Spontaneous electrical activity was obtained from the guinea pig antrum
in the presence of nifedipine. Slow-wave activity was recorded from
cells recognized by injection of neurobiotin after recording of
intracellular activity. Impalements of ICC gave large slow waves with a
rate of rise that was much faster than that of slow waves from smooth
muscle cells. Recordings from ICC (a) and smooth muscle
cells (b) were recorded simultaneously. The slow wave
appears first in the ICC. Reproduced from Fig. 3 in Dickens et al.
(6).
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Fig. 4.
The pylorus is a region where slow-wave propagation is
completely blocked. Propagation of slow waves and action potentials was
recorded with a set of 240 electrodes on the pyloric region of the cat.
This figure was reproduced and modified with permission from Fig. 3 in
Lammers et al. (17).
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W/Wv mutant mice provided the first real evidence that ICC-AP were
critical for the generation of slow-wave activity (15, 32). The stomachs of W/Wv mice do not have ICC-IM but normal ICC-AP, and indeed slow-wave activity can be readily recorded (2). The normal fundus does not have ICC-AP, and no
slow-wave activity is present. Early work in the 1970s from the
laboratories of Szurszewski (7) and Tomita
(24) described gastric slow-wave activity as being
composed of two components. Apart from the regular basic slow wave, a
secondary regenerative component was evident. On stimulation (by
cholinergic agents for example), the duration and amplitude of the slow
wave increased, and this secondary component was shown to be associated
with contraction. In other words, in addition to the generation of
action potentials, excitation causes changes in slow-wave activity that
contribute to contractile activity. An increase in slow-wave duration
may cause a decrease in frequency. Thus changes in slow-wave frequency
can be a normal part of stomach functioning. Indeed, the slow-wave
frequency decreases after a meal (37). Interestingly,
Dickens et al. (5a) observed that the second component was
missing in W/Wv mice and put forward the hypothesis that ICC-IM are
involved in its generation. This was also suggested by Tomita and
co-workers studying the guinea pig antrum (13). An
alternative explanation could be that, without ICC-IM, intrinsic
stimulation from enteric nerves through ICC-IM is diminished, which may
lead to a poorly developed secondary component. Furthermore, lack of
ICC may alter smooth muscle function because of loss of the
hyperpolarizing influence of carbon monoxide production by ICC
(22, 26, 44). Understanding of the precise genetic
differences between mutant mice will eventually help to discriminate
between these possibilities (31).
Mutant mice have also contributed to our knowledge about the
intercellular mechanisms that trigger pacemaker ion channels that
generate the ICC slow wave (Fig. 5). In
inositol 1,4,5-trisphosphate (IP3) knockout mice, no
slow-wave activity is recorded (30), providing further
evidence for a role of IP3 in the activation of pacemaker
currents (19, 42).

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Fig. 5.
Pacemaking in ICC may depend on inositol
1,4,5-trisphosphate (IP3)-stimulated calcium release.
Spontaneous electrical activity recorded from circular smooth muscle of
the gastric antrum of wild-type and IP3 knockout mice. Slow
waves with action potentials are recorded from wild-type mice, but only
bursts of action potentials are generated in the mutant mice, similar
to results obtained in W/Wv mutant mice (20).
Reproduced from Fig. 11 in Suzuki (29).
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THE ELECTROGASTROGRAM |
Does the electrogastrogram (EGG) reflect activity from ICC?
Because the slow wave is initiated by ICC and because the EGG primarily
records the slow-wave activity, ICC activity will be reflected in the
EGG. However, the musculature and the enteric nervous system contribute
to the overall appearance of the slow wave that is ultimately generated
by the muscle cells and is picked up by EGG recording electrodes.
Hence, abnormalities in the EGG do not necessarily reflect only
abnormal ICC functioning. A change in slow-wave frequency that is
established to occur after a meal (37) is likely a
consequence of neural stimulation of the ICC and/or the musculature
(see above). Apart from artifacts that can easily slip into the EGG
analysis (38), the EGG as a measure of gastric motility is
not well established. Although the slow wave itself (in addition to
action potentials that are poorly, if at all, measured in the EGG)
contributes to contractile activity, reliable correlations between such
EGG changes and in vivo motor changes have not yet been established.
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ICC AND PACING |
Because ICC are pacemaker cells, can they be paced to alter motor
activity? There is no question that electrical stimulation can increase
slow-wave frequency or restore an abnormal slow-wave rhythm (Fig.
6). It has also been established that one
can drive the frequency of the distal antral slow wave to frequencies
higher then the intrinsic slow wave of the corpus and thereby force the direction of slow-wave propagation to occur from the pyloric region to
the corpus. But can pacing restore delayed gastric emptying? Over the
years, a lot of attention has been given to this possibility. First, it
must be stated that in many cases in which pacing was considered for
improvement of gastric emptying, no firm evidence existed that abnormal
slow-wave activity was the primary cause of abnormal gastric emptying.
Second, it was often assumed that an increase in slow-wave frequency
would lead to an increase in rate of emptying. Two factors have to be
in place for normal gastric emptying to occur with respect to the role
of the distal stomach. A normal, aborally propagating slow wave has to
occur, and this slow-wave activity has to be accompanied by pressure
waves of sufficient amplitude (14). Thus the slow waves
have to be bearing sufficient action potentials (spiking activity),
which is usually provided by excitatory stimulation from the enteric
nervous system. Hence, in cases in which abnormal emptying is primarily
caused by insufficient excitation provided by the enteric nervous
system, pacing the stomach to a higher frequency will not help. Even if the slow-wave rhythm is abnormal and the pacing would force it into a
normal, aborally propagating rhythm, emptying might still not be
improved because of a lack of forceful contractile activity (12). When an abnormal rhythm is the primary cause of
delayed emptying, pacing may restore peristalsis (21).
Electrical stimulation that causes pacing of slow waves may also
initiate action potentials (Fig. 6), but this is not common. A
beginning has been made with the electrical stimulation of excitatory
nerves within the stomach to improve gastric emptying
(23).

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Fig. 6.
Slow waves in the human stomach can be paced. Slow-wave activity
was recorded with subcutaneously placed electrodes by Dr. W. Waterfall.
The first recording is control slow-wave activity. The second recording
is paced slow-wave activity at a higher frequency, with the pacing
identified in the bottom trace. Note that the sharp peak
preceding the paced slow waves is a stimulus artefact. Note that the
electrical stimulation caused some slow waves to carry action
potentials.
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THE PYLORUS AND ICC PATHOPHYSIOLOGY |
The normal pylorus has a rich complement of ICC-IM. These cells
are markedly altered and reduced in number in pyloric stenosis as
assessed by both immunohistochemistry and electron microscopy (18, 35). Abnormal motility in pyloric stenosis is likely a combination of lack of nitrergic nerves and ICC-IM, and both may
develop to normal proportions over time. ICC-AP may serve as pacemaker
cells orchestrating the isolated pyloric contractions but are unlikely
to assist in coordination between gastric and duodenal activity. In a
recent elegant study by Lammers and co-workers (17), the
pylorus was shown as an area where slow-wave propagation is completely
blocked (Fig. 4). This serves to allow the stomach and small intestine
to generate independent propagating motor patterns involving ICC.
Pyloric stenosis might be a case of delayed ICC development
(36). Lack of ICC is also implicated in a study of
idiopathic gastric perforation, in which three of seven neonates have
complete absence of ICC and ICC were reduced in the other four
(25). ICC-AP are probably functionally mature well before birth since strong slow wave rhythms were observed at 29 wk of gestation (3). Structurally, however, ICC may not be fully developed (4), which is a reminder that functional and
structural maturity may not be perfectly correlated.
Immunohistochemistry can show Kit-positive cells (excluding mast cells)
that are likely to be ICC in the human gut musculature. The advantage
of this technique is that it can give an overview of ICC distribution in sections using conventional immunohistochemistry and in whole mounts
using confocal microscopy. Some quantification can also be attempted.
Electron microscopy can identify ICC positively and can also provide
details of structural abnormalities that may be undetected with
immunohistochemistry (39). With the use of these
techniques, the possible implication of ICC in the pathophysiology of
gastric motor disorders will be elucidated in the coming years.
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ACKNOWLEDGEMENTS |
The support of the Canadian Institutes of Health Research is
gratefully acknowledged.
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FOOTNOTES |
Abbreviations used for the various subtypes of ICC are those
established by Thuneberg (9, 16, 33).
Address for reprint requests and other correspondence: J. Huizinga, McMaster Univ., 1200 Main St. West, Health Sciences Bldg. Rm
3N5C, Hamilton L8N 3Z5, Canada (E-mail:
huizinga{at}mcmaster.ca).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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