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Keywords:

  • enteric motor neurotransmission;
  • interstitial cells of Cajal;
  • gastrointestinal motility;
  • smooth muscle

Abstract

  1. Top of page
  2. Abstract
  3. Involvement of icc in neuroeffector transmission
  4. Identification of specific populations of icc and their association with enteric nerves
  5. Functional innervation of icc and the consequences of their loss in animal models
  6. Summary
  7. Acknowledgments
  8. References

Specialized cells known as interstitial cells of Cajal (ICC) are distributed in specific locations within the tunica muscularis of the gastrointestinal tract and serve as electrical pacemakers, active propagation pathways for slow waves, and mediators of enteric motor neurotransmission. Recent morphological studies have provided evidence that motor neurotransmission in the gut does not occur through loosely defined synaptic structures between nerves and smooth muscle, but rather via synaptic-like contacts that exist between varicose nerve terminals and intramuscular ICC (ICC-IM). ICC-IM are coupled to smooth muscle cells via gap junctions and electrical responses elicited in ICC are conducted to muscle cells. Electrophysiological studies of the stomach of wild-type and mutant animals that lack ICC-IM have provided functional evidence for the importance of ICC in cholinergic and nitrergic motor neurotransmission. The synaptic-like contacts between nerve terminals and ICC-IM facilitate rapid diffusion of transmitters to specific receptors on ICC. ICC-IM also play a role in generating unitary potentials in the stomach that contribute to the excitability of the gastric fundus and antrum.


Involvement of icc in neuroeffector transmission

  1. Top of page
  2. Abstract
  3. Involvement of icc in neuroeffector transmission
  4. Identification of specific populations of icc and their association with enteric nerves
  5. Functional innervation of icc and the consequences of their loss in animal models
  6. Summary
  7. Acknowledgments
  8. References

Visceral organs containing smooth muscle cells are innervated by nerve terminals which arise from either sympathetic, parasympathetic or enteric nerve cells. In the gastrointestinal tract, the tunica muscularis is innervated by both excitatory and inhibitory motor nerve fibres from the enteric nervous system.1 It has been viewed routinely that motor innervation to the muscle layers within gastrointestinal muscles occurs via loosely defined structures, and neurotransmitters are released en passage as action potentials invade nerve varicosities.2 The distance a neurotransmitter can diffuse within the extracellular fluid before it directly activates specific receptors, is metabolized, taken up, or diluted to functionally insignificant levels defines the ‘innervated’ population of smooth muscle cells in this concept. However when this hypothesis of en passage innervation has been tested directly it has been found only rarely to be correct. En passage innervation has been challenged by morphological studies in which autonomically innervated organs have been serially sectioned and examined ultrastructurally. Reconstructions of nerve varicosities and closely apposed smooth muscle cells have revealed distinct neuroeffector junctions in several organs,3,4 suggesting that there are specific target areas on postjunctional cells that provide specialized mechanisms for reception and transduction of neurotransmitter signals. Further, neurally released transmitters also appear to activate specific sets of postsynaptic receptors located close to the sites of neurotransmitter release.5 Evidence now exists that close morphological contacts between enteric nerve terminals and postjunctional cells are an important feature of motor innervation in the gastrointestinal tract. It is also apparent that in several, but not all gastrointestinal tissues, neuroeffector junctions are more complicated than simple contacts between nerve terminals and smooth muscle cells. Several lines of evidence now support the concept first proposed by Cajal6 and later by Roman and coworkers7 and Daniel & Posey-Daniel8 that neuroeffector junctions exist between enteric nerve terminals and interstitial cells of Cajal (ICC) in several regions of the gastrointestinal tract, with effective neurotransmission resulting from the activation of specific sets of receptors on ICC rather than receptors present on smooth muscle cells (see Fig. 1).

image

Figure 1. The classical concept of motor innervation of gastrointestinal muscles is shown in (A). It is believed that neuroeffector innervation occurs when transmitter is released from neurovesicles present in nerve varicosities as action potentials invade neural processes. Functional innervation is thought to occur through loosely defined synaptic structures and the distance a transmitter can diffuse before it is metabolized, taken up, or diluted to functionally insignificant levels defines the ‘innervated’ population of cells. En passage innervation in certain regions of the GI tract has been challenged by more recent morphological and physiological studies and the current concept of motor innervation is shown in (B). Close synaptic-like contacts exist at neuroeffector junctions between varicose nerve terminals and interstitial cells of Cajal and not with smooth muscle cells. (CA′) shows double-labelling of excitatory enteric motor nerves (identified with vesicular acetylcholine transporter-like immunoreactivity, arrows, white punctuate structures) and intramuscular ICC (ICC-IM identified with Kit-like immunoreactivity, arrowheads, grey) in the murine fundus. Enteric nerve fibres were closely apposed to ICC-IM for several hundred microns. Panels CB′ and CC′ show electron micrographs of varicose nerve terminals containing large cored and small clear vesicles and ICC-IM. A synaptic-like junction (arrow) with pre- and postsynaptic densifications of the plasma membranes can be observed between an enteric nerve varicosity and ICC. (D) Postjunctional neural response in a wild-type gastric fundus in response to electric field stimulation (0.5 ms, single pulse delivered as indicated by the arrow). Under control conditions the neural response consists of a cholinergic excitatory junction potential followed by a more sustained nitric-oxide dependent inhibitory junction potential. (E) Recording from a W/WV mutant which lacks ICC-IM in the stomach, both the cholinergic and nitric oxide-dependent neural responses are absent (electrical stimulation indicated by the arrow). Enteric nerve fibres are normal in number and are capable of releasing ACh (measured by the fractional release of [14C]choline in these mutant animals. Note also the difference in the basal noise of recordings in wild-type and W/WV mutants. Analysis has revealed that this noise is made up of unitary potentials that originate in ICC-IM. The authors are grateful for the artwork provided by Elizabeth A. H. Beckett and Geoffrey D. Sanders in (A) and (B). (CB′) and (CC′) are reproduced from Horiguchi et al. 200334 with kind permission of Springer-Verlag.

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Identification of specific populations of icc and their association with enteric nerves

  1. Top of page
  2. Abstract
  3. Involvement of icc in neuroeffector transmission
  4. Identification of specific populations of icc and their association with enteric nerves
  5. Functional innervation of icc and the consequences of their loss in animal models
  6. Summary
  7. Acknowledgments
  8. References

The discovery that ICC express c-kit, the proto-oncogene that encodes the receptor tyrosine kinase, Kit,9–12 has offered a simple and reliable immunohistochemical method for determining the structure and distribution of ICC networks. Immunohistochemistry, using double labelling with Kit and markers for specific populations of enteric nerves has also provided us with an increased understanding of the relationship that is formed between excitatory and inhibitory nerve terminals and ICC. Morphological studies now supported by functional evidence suggest that at least three separate functional groups of ICC exist. In most regions of the gastrointestinal tract, a network of ICC are located within the intermuscular space at the level of the myenteric plexus (ICC-MY) between the circular and longitudinal muscle layers. ICC-MY are the pacemaker cells in the stomach and small intestine that trigger the generation of slow waves in the tunica muscularis. The role of these cells in slow-wave generation and propagation is discussed by Sanders et al.13 (this issue). A second population of ICC (referred to as intramuscular ICC or ICC-IM) are found distributed within the muscle layers of the GI tract and are innervated preferentially by enteric motor nerves. In the small intestine ICC-IM, rather than being evenly distributed within the muscle layers, are concentrated at the inner surface of the circular layer at the region of the deep muscular plexus. These ICC-DMP also receive preferential innervation and may be a specialized type of ICC-IM in the small intestine.

Functional innervation of icc and the consequences of their loss in animal models

  1. Top of page
  2. Abstract
  3. Involvement of icc in neuroeffector transmission
  4. Identification of specific populations of icc and their association with enteric nerves
  5. Functional innervation of icc and the consequences of their loss in animal models
  6. Summary
  7. Acknowledgments
  8. References

Structural proximity of cells with enteric nerve terminals does not necessarily signify a functional innervation. Target cells must receive inputs from motor nerves and express receptors and effectors capable of receiving and transducing transmitter signals into postjunctional responses. ICC isolated and cultured from the canine colon have shown physiological responses to major neurotransmitter substances,14 suggesting these cells are able to recognize and respond to transmitters. Studies that monitored changes in second messenger content after nitrergic stimulation provided the first evidence that ICC were innervated functionally. Levels of cyclic GMP (cGMP), detected with immunohistochemistry, were enhanced in ICC by enteric nerve stimulation and following exogenous application of sodium nitroprusside in the canine colon and guinea-pig small intestine. Enhanced cGMP levels were blocked with the nitric oxide (NO) antagonist, l-nitroarginine.15,16 It has also been shown that ICC-DMP of the small intestine of several species express neurokinin 1 (NK1) receptors and somatostatin 2 A receptors.17–19 After exposure to substance P, NK1 receptors were internalized within ICC-DMP in the guinea-pig small intestine and receptor immunoreactivity aggregated in the cytoplasm.20 Recent molecular studies using reverse transcription-polymerase chain reaction (RT-PCR) confirm the expression of neurotransmitter receptors and have shown that muscarinic receptors (M2 and M3), neurokinin receptors (NK1 and NK3) and vasoactive intestinal polypeptide (VIP) receptors (VIP-1) are expressed in ICC of the murine GI tract, as shown with these techniques.21

Morphological and molecular data have confirmed that ICC are situated very close to enteric neurones, and ICC express functional receptors that are required for enteric motor neurotransmission. A major question remaining from these studies was whether the innervation of ICC is fundamental or incidental to neural control of the GI tract. Mutant animals lacking specific classes of ICC were an ideal model to address this question.

The importance of Kit signalling for the development and maintenance of ICC provided a means to manipulate the development of ICC networks. Neutralizing antibodies for Kit blocked the development of ICC,10,22 and the use of W mutants became an important breakthrough for studies examining the physiological role of ICC.9,11,23–25 Specific populations of ICC were lost in W/WV animals that have reduced Kit expression and Sl/Sld animals that lack the particulate form of stem cell factor, the natural ligand for Kit. These included the absence of ICC-MY in the myenteric region of the small intestine9,11 that is associated with a loss of pacemaker activity in this tissue. ICC-IM are also absent in the fundus and antrum of the stomach23,25,26 and in the lower oesophageal and pyloric sphincters.27 The absence of ICC-IM in the stomach provided the first opportunity to test the physiological role of these cells. ICC-IM were the most likely population to be involved in neurotransmission as they are interposed between varicose nerve terminals and smooth muscle cells. In wild-type mice, stimulation of intrinsic nerves in the fundus evokes a complex response consisting of cholinergic excitatory and nitrergic inhibitory components. After blocking the nitrergic component, nerve stimulation evokes EJPs. These events are blocked by atropine and enhanced by inhibiting choline esterase with neostigmine. A slower component of depolarization following the fast EJP appears after neostigmine that is also blocked by atropine. ICC-IM are present in wild-type fundus muscles and contribute a noisy discharge above the resting membrane potential.23,28 These events are also present in the gastric antrum and are known as unitary potentials.29

In W/WV or Sl/Sld mice, which lack the normal ligand for Kit, ICC-IM are missing. Excitatory and inhibitory components of responses to intrinsic nerve stimulation are greatly attenuated in these muscles.23–25,28 Other than the loss of ICC-IM and responses to enteric nerve stimulation, fundus muscles appear normal, contain varicose processes of enteric neurones at normal density, release neurotransmitter and generate mechanical responses to acetylcholine (ACh) and NO.24,28 Cholinergic nerve terminals were also shown to be functional in these mutants by the fact that neostigmine treatment caused atropine sensitive neurally evoked slow depolarizations to develop in muscles lacking ICC-IM.

The simplest explanation for these findings is that both inhibitory and excitatory nerve terminals selectively target ICC-IM. When these cells are absent in gastric muscles neurotransmitters released fail to reach ‘extra-junctional’ receptors located on smooth muscle cells at sufficiently high concentrations to elicit responses in W/WV or Sl/Sld muscles unless the transmitter is preserved (such as occurs with ACh after neostigmine treatment). Preservation of ACh allows activation of receptors with slow activation kinetics that are probably located on smooth muscle cells.30

Qualitatively similar observations have been made in experiments on the mouse antrum. In wild-type muscles nerve stimulation evokes a complex inhibitory junction potential (IJP), consisting of an initial apamin-sensitive IJP and a slower nitrergic IJP; the inhibitory responses are followed by an atropine-sensitive excitatory response. In antrums of W/WV mice the initial apamin-sensitive component is present, but both the nitrergic and cholinergic responses were absent.25 Retention of purinergic responses in W/WV muscles is extremely interesting and may mean that these responses are mediated by activation of P2Y receptors on smooth muscle cells or other cells in the muscle wall.31 Thus, a parallel innervation of gastric muscle occurs possibly by transmitters targeting different cellular components.

Results obtained from studies on murine tissues deficient in ICC-IM were also supported by analyses of neuroeffector transmission in guinea-pig antrum. In the circular layer of the gastric antrum, after the effects of inhibitory transmitters are abolished, cholinergic nerve stimulation initiates an increase in unitary potentials and regenerative responses that appear to be due to summation of unitary potentials. These responses are identical to those initiated when ICC-IM were depolarized with current.29 Responses to both neurally released ACh and direct depolarization depend upon the release of Ca2+ from inositol 1,4,5-trisphosphate (IP3)-sensitive stores. Furthermore, the postjunctional pathway activated by ACh in ICC-IM involves a voltage-dependent mechanism because moderate hyperpolarization blocked activation of the pathway. This may be due to voltage-activated production of IP3 and a subsequent increase in intracellular calcium. In contrast, smooth muscle responses to ACh are not affected greatly by membrane hyperpolarization.

Another important function of ICC-IM is to mediate changes in pacemaker activity caused by neural inputs. Summation of unitary potentials into regenerative potentials can phase advance the ongoing pacemaker activity and elicit premature slow waves or increase the frequency of slow waves if neural activity is sustained.32,33 Thus, neural pacing of slow waves is mediated by responses first initiated in ICC-IM. Neurally released NO also selectively targets ICC-IM,25 and an analysis of nitrergic-IJPs in the antrum indicates that neurally released NO suppresses the resting discharge of unitary potentials.25 Taken together, these experiments suggest that most neuronal inputs in the antrum are mediated via ICC-IM. Thus, it can be assumed that loss of these cells in pathophysiological disorders might appear as a neuropathy and produce dramatic loss of neural control of motility.

Although this review has focused on the morphological and physiological evidence that implicates ICC in enteric motor neurotransmission, evidence is also accumulating to suggest that ICC-IM may also serve a role in afferent neural signalling in the gastrointestinal tract. Vagal afferent nerve endings, labelled in vivo with injections of the carbocyanine dye Dil into the nodose ganglia can terminate as intramuscular arrays within the muscle wall of the stomach. These endings form close appositions with ICC-IM, upon which they appeared to form multiple spiny appositions or varicosities that may provide a role in stretch perception.35 Furthermore, W/WV and Sl/Sld mutants that lack ICC-IM have significantly reduced numbers of vagal intramuscular arrays in their forestomachs compared to wild-type controls. There is a reduction of 63% in the circular and 78% in longitudinal muscles in W/WV mutants and 53% in the circular and 68% in longitudinal muscles of Sl/Sld mutants.36,37 These data would suggest that ICC-IM are important for the normal development or maintenance of vagal intramuscular arrays in the stomach. Recent immunohistochemical studies have also shown a close apposition between nerve fibres labelled with antibodies directed against the vallinoid receptor VR1 and ICC-IM in the stomach.38 VR1 also known as the TRPV1 receptor, are located on sensory nerve endings in the gastrointestinal tract termed nociceptors that are sensitive to a variety of stimuli including capsaicin. Because of its ability to respond to a variety of noxious stimuli the VR1 receptor has been described as a molecular integrator of chemical and physical stimuli that elicit pain. In the stomach the majority of VR1-like immunoreactive nerve fibres appeared to be of a spinal origin. Their close association with ICC-IM would suggest that ICC-IM may play also play a role in sensory perception through spinal pathways.38

Summary

  1. Top of page
  2. Abstract
  3. Involvement of icc in neuroeffector transmission
  4. Identification of specific populations of icc and their association with enteric nerves
  5. Functional innervation of icc and the consequences of their loss in animal models
  6. Summary
  7. Acknowledgments
  8. References

The neuroeffector junction in gastrointestinal muscles is not as simple as many investigators thought previously. Morphological and functional evidence indicates that the enteric neuromuscular junction is composed of at least three cell-types. Neurotransmitter is concentrated in and released from varicose regions along motor axons. These terminals make very close synapse associations with ICC-IM, which are interposed between the nerve terminals and the smooth muscle syncytium. ICC play a critical role in reception and transduction of both excitatory and inhibitory neurotransmission. ICC-IM form gap junctions with smooth muscle cells and electrical responses generated in ICC are conducted to neighbouring smooth muscle cells. By this contact ICC can regulate the contractile responses of the smooth muscle and affect motor patterns in GI muscles. Analyses of neuroeffector transmission shows that transmitters released from enteric neurones produce effects attributable to actions mediated via ICC-IM. Recent morphological evidence showing close apposition between vagal and spinal afferents and ICC-IM within the muscle wall also supports a role for ICC-IM as possible integrators for in-series stretch-dependent changes in the stomach.

References

  1. Top of page
  2. Abstract
  3. Involvement of icc in neuroeffector transmission
  4. Identification of specific populations of icc and their association with enteric nerves
  5. Functional innervation of icc and the consequences of their loss in animal models
  6. Summary
  7. Acknowledgments
  8. References
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