Multifunctional rapidly adapting mechanosensitive enteric neurons (RAMEN) in the myenteric plexus of the guinea pig ileum

Jiang

American Journal of Physiology-Cell Physiology

et al. 2015

Mittal RK. Inhibitory motor neurons of the esophageal myenteric plexus are mechanosensitive. Am J Physiol Cell Physiol 308: C405-C413, 2015. First published December 24, 2014; doi:10.1152/ajpcell.00159.2014.-Mechanosensitivity of enteric neurons has been reported in the small intestine and colon, but not in the esophagus. Our earlier in vivo studies show that mechanical stretch of the esophagus in the axial direction induces neurally mediated relaxation of the lower esophageal sphincter, possibly through mechanosensitive motor neurons. However, this novel notion that the motor neurons are mechanosensitive has not been examined in isolated esophageal myenteric motor neurons. The goal of our present study was to examine the mechanosensitivity of esophageal motor neurons in primary culture and elucidate the underlying molecular mechanisms. Immmunocytochemical analysis revealed that Ͼ95% cells were positive for the neuronal marker protein gene product 9.5 and that 66% of these cells costained with protein gene product 9.5 and neuronal nitric oxide (NO) synthase. Hypotonic solution induced an increase in the cytoplasm volume in all cells that was independent of extracellular Ca 2ϩ . Hypotonic solution and mechanical stretch induced cytoplasmic free Ca 2ϩ signaling in ϳ65% of neurons in the presence, but not absence, of extracellular Ca 2ϩ . Neurons grown on the elastic membrane responded to mechanical stretch by an increase in neuronal size and Ca 2ϩ signaling simultaneously. Hypotonic stretch-induced cytoplasmic free Ca 2ϩ signaling was not affected by extracellular Mg 2ϩ , 5-nitro-2-(3-phenylpropylamino)benzoic acid, and nifedipine but was attenuated by 2-aminoethoxydiphenyl borate, Gd 3ϩ , and Grammostola mechanotoxin 4, blockers of the stretch-activated ion channels. In ϳ57% of the neurons, hypotonic stretch also induced Ca 2ϩ -dependent cytoplasmic NO production, which was abolished by Grammostola mechanotoxin 4. These results prove that the esophageal inhibitory motor neurons possess a mechanosensitive property and also provide novel insights into the stretch-activated ion channel-Ca 2ϩ -NO signaling pathway in these neurons. neuronal nitric oxide synthase; nitric oxide production; cytoplasmic free calcium; stretch-activated cation channels THE ENTERIC NERVOUS SYSTEM regulates gastrointestinal (GI) functions, such as digestion, absorption, secretion, motility, and sensation (1, 14, 37). The enteric nervous system contains three types of neurons: 1) sensory neurons [intrinsic primary afferent neurons (IPANs)], 2) interneurons, and 3) motor neurons (1, 14). The latter are further subdivided into excitatory and inhibitory motor neurons on the basis of their regulatory functions (1, 15): excitatory motor neurons contain neurotransmitters, such as acetylcholine, substance P, and glutamate (14), and inhibitory motor neurons contain nitric oxide (NO), ATP, and vasoactive intestinal polypeptide (14, 37).Similar to neurons in the rest of the GI tract, neurons in the wall of esophagus also play an important role in the s...

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Inhibitory motor neurons of the esophageal myenteric plexus are mechanosensitive

Jiang

American Journal of Physiology-Cell Physiology

et al. 2015

“…In addition to this, our results show that expression of MrgE and MrgF is not limited to IPANs. A recent study revealed that mechanosensitivity is a property of more enteric neuronal subpopulations than generally assumed and that every subpopulation of enteric neurons is to some extent sensitive to mechanical distortion, which might imply that the current concept of sensory transmission in the ENS needs to be revised (Mazzuoli and Schemann 2009). In previous studies in rat, MrgA, MrgC and MrgF mRNAs were detected in the cerebellum, i.e.…”

Section: Discussionmentioning

confidence: 98%

The effect of inflammation on the expression and distribution of the MAS-related gene receptors MrgE and MrgF in the murine ileum

Avula

Buckinx

Alpaerts

et al. 2011

Histochem Cell Biol

The MAS-related gene (Mrg) receptor MrgE has been suggested to be expressed at all tissue levels involved in pain sensation and to influence the expression of another Mrg receptor, MrgF. Given the knowledge on the role of the enteric nervous system (ENS) in sensation, and the plasticity of enteric neurons during intestinal inflammation, it can be hypothesized that MrgE is expressed in enteric neurons, and that MrgE and MrgF change expression in intestinal inflammatory conditions. Therefore, we aimed to reveal the expression details of MrgE and MrgF in the murine ileum in normal and inflamed conditions. Using reverse transcriptase-PCR, quantitative-PCR and immunohistochemistry, we compared the ileum of non-inflamed control mice with that of two models of intestinal inflammation, i.e. intestinal schistosomiasis and chemically induced ileitis. MrgE and MrgF mRNAs were detected in control and inflamed conditions. MrgE and MrgF mRNAs showed a trend towards downregulation during intestinal schistosomiasis and a significant reduction during ileitis. MrgE and MrgF receptors were expressed in distinct enteric neuronal subpopulations, such as the sensory, secretomotor and vasodilator neurons, and in nerve fibres in the tunica muscularis and lamina propria of control and inflamed ileum. Only a minor proportion of enteric neurons co-expressed MrgE and MrgF. The number of enteric neurons expressing MrgE and MrgF receptors was significantly reduced during intestinal schistosomiasis and ileitis. This is the first report on the expression of MrgE and MrgF in the ENS in (patho)physiological conditions. The expression of MrgE and MrgF in enteric neurons was negatively affected by inflammation.

Advances in Experimental Medicine and Biology

“…It has been more recently discovered that distortion also excites other neurons, for example interneurons, in the enteric nerve circuits [79][80][81], indicating that reflexes are not uniquely initiated or modulated through type II neurons. Cell bodies of multi-axonal IPANs are 10-30 % of neurons in the submucosal and myenteric ganglia of the small and large intestines.…”

Section: Intrinsic Sensory Neurons (Ipans)mentioning

confidence: 99%

The Enteric Nervous System and Gastrointestinal Innervation: Integrated Local and Central Control

Furness

Callaghan

Rivera

et al. 2014

655

648

The digestive system is innervated through its connections with the central nervous system (CNS) and by the enteric nervous system (ENS) within the wall of the gastrointestinal tract. The ENS works in concert with CNS reflex and command centers and with neural pathways that pass through sympathetic ganglia to control digestive function. There is bidirectional information flow between the ENS and CNS and between the ENS and sympathetic prevertebral ganglia.The ENS in human contains 200-600 million neurons, distributed in many thousands of small ganglia, the great majority of which are found in two plexuses, the myenteric and submucosal plexuses. The myenteric plexus forms a continuous network that extends from the upper esophagus to the internal anal sphincter. Submucosal ganglia and connecting fiber bundles form plexuses in the small and large intestines, but not in the stomach and esophagus. The connections between the ENS and CNS are carried by the vagus and pelvic nerves and sympathetic pathways. Neurons also project from the ENS to prevertebral ganglia, the gallbladder, pancreas and trachea.The relative roles of the ENS and CNS differ considerably along the digestive tract. Movements of the striated muscle esophagus are determined by neural pattern generators in the CNS. Likewise the CNS has a major role in monitoring the state of the stomach and, in turn, controlling its contractile activity and acid secretion, through vago-vagal reflexes. In contrast, the ENS in the small intestine and colon contains full reflex circuits, including sensory neurons, interneurons and several classes of motor neuron, through which muscle activity, transmucosal fluid fluxes, local blood flow and other functions are controlled. The CNS has control of defecation, via the defecation centers in the lumbosacral spinal cord. The importance of the ENS is emphasized by the life-threatening effects of some ENS neuropathies. By contrast, removal of vagal or sympathetic connections with the gastrointestinal tract has minor effects on GI function. Voluntary control of defecation is exerted through pelvic connections, but cutting these connections is not life-threatening and other functions are little affected.