Are interstitial cells of Cajal plurifunction cells in the gut?

Abstract

The proposed functions of the interstitial cells of Cajal (ICC) are to 1) pace the slow waves and regulate their propagation, 2) mediate enteric neuronal signals to smooth muscle cells, and 3) act as mechanosensors. In addition, impairments of ICC have been implicated in diverse motility disorders. This review critically examines the available evidence for these roles and offers alternate explanations. This review suggests the following: 1) The ICC may not pace the slow waves or help in their propagation. Instead, they may help in maintaining the gradient of resting membrane potential (RMP) through the thickness of the circular muscle layer, which stabilizes the slow waves and enhances their propagation. The impairment of ICC destabilizes the slow waves, resulting in attenuation of their amplitude and impaired propagation.2) The one-way communication between the enteric neuronal varicosities and the smooth muscle cells occurs by volume transmission, rather than by wired transmission via the ICC. 3) There are fundamental limitations for the ICC to act as mechanosensors.4) The ICC impair in numerous motility disorders. However, a cause-and-effect relationship between ICC impairment and motility dysfunction is not established. The ICC impair readily and transform to other cell types in response to alterations in their microenvironment, which have limited effects on motility function. Concurrent investigations of the alterations in slow-wave characteristics, excitationcontraction and excitation-inhibition couplings in smooth muscle cells, neurotransmitter synthesis and release in enteric neurons, and the impairment of the ICC are required to understand the etiologies of clinical motility disorders. smooth muscle; slow waves; enteric neurons; excitation-contraction coupling; peristaltic reflex; motility disorders; volume transmission; synaptic transmission, ICC THE INTERSTITIAL CELLS WERE characterized originally by Raymond V. Cajal (20,21). These cells got his attention and that of others because they are intercalated between the autonomic nerves and the effector cells. On the basis of the understanding of the interneuronal communication in the central nervous system (CNS) at that time, Cajal proposed that the intercalating cells [later called the interstitial cells of Cajal (ICC)] mediate the transmission of signals from the autonomic neurons to the smooth muscle cells. A few years later, Keith (84) observed a collar of similar cells in the myenteric plexus of the rat ileocecal junction. He was looking for a pacemaker of the gut smooth muscle electrical activity because a few years earlier he had identified such a pacemaker in the sinoatrial node of the heart. He hypothesized that those interstitial cells were the pacemaker cells in the gut. In the late 1960s and early 1970s, several investigators described a plexus of the ICC within the myenteric and submucosal plexi of the small and large intestines. They also identified close connections between the enteric axonal varicosities and ICC processes on one side and g...

Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity

“…Functional analysis of ICC has provided crucial insights into the generation of pacemaking currents and slow-wave activity in the gut in health and disease 4,7,17,36,37 . However, because of the general lack of genetic studies targeting ICC or signalling pathways in ICC, it is still highly controversial whether ICC are involved in enteric neurotransmission [9][10][11]16 . These controversies are mainly because of the use of murine hypomorphic c-Kit germline mutants (like the W/W v model) in nearly all studies investigating ICC function 9,11,16 .…”

“…There has been a long standing controversy whether ICC have a role in the regulation of excitatory and inhibitory neurotransmission, besides generating slow waves [8][9][10][11][12][13][14][15][16]26 . In small intestinal circular smooth muscle cells, ongoing slow waves with a frequency of B30-35 cycles per min (Fig.…”

“…Previous studies provided clear evidence that ICC generate a rhythmic pacemaker current, which manifests itself as slow waves in the membrane potential of smooth muscle cells, resulting in rhythmic bowel contractions 4,7,8 . However, a role of ICC in the transmission of excitatory and inhibitory signals from enteric neurons to smooth muscle cells is highly controversial and remains an outstanding question [8][9][10][11][12][13][14][15][16] . This is mainly because of the general lack of models and systems to study ICC function in adult animals at genetic level 9,11,16 .…”

Analysis of spatiotemporal pattern and quantification of gastrointestinal slow waves caused by anticholinergic drugs

“…Whether neuronal input to ICC is significant is a matter of debate, [1][2][3][4][5][6][7]17,26 however growing evidence suggests that ICC play a role in enteric neurotransmission. It has been shown that intramuscular ICC is closely associated with myenteric motor neurons, forming synapse-like junctions with nerve varicosities.…”

“…1 Currently under debate is the exact role and significance of ICC in enteric neurotransmission. [1][2][3][4][5][6][7] Enteric neurons utilize acetylcholine as their primary neurotransmitter, 8 and anticholinergic drugs are well known to block enteric neurotransmission and result in GI adverse effects, including constipation. 9,10 What is as yet unknown is the effect of anticholinergic drugs on the background rhythmic contractions driven by slow waves.…”