Distribution of 5-Ht4 receptors in wild-type mice and analyses of intestinal motility in 5-Ht4 knockout mice

Fiorica‐Howells, Elena; Liu, Min-Tsai; Ponimaskin, Evgeni; Li, Zhishan; Compan, Valérie; Hen, René; Gingrich, Jay A.; Gershon, Michael D.

doi:10.1016/s0016-5085(03)81723-7

Cited by 18 publications

(17 citation statements)

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“…The potential of a trophic transmitter, serotonin, and receptors to remodel or regenerate enteric neural supply has been the focus of research by Gershon’s group. Colorectal motility was significantly slower in 5‐HT 4 knockout mice lacking 5‐HT 4 receptors than in their wild‐type littermates 93 . Neuronal size and the proportion of myenteric neuronal NOS (nNOS)‐immunoreactive neurons were decreased in knockout mice at 12 months.…”

Section: Serotonergic Mechanisms In Maintenance and Survival Of Entermentioning

confidence: 99%

Enteric neurodegeneration in ageing

Camilleri

Cowen

Koch

2008

Neurogastroenterology Motil

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The objective of this article is to review the clinical presentation and neurobiology of degeneration of the enteric nervous system with emphasis on human data where available. Constipation, incontinence and evacuation disorders are frequently encountered in the ageing population. Healthy lower gastrointestinal function is essential for successful ageing as it is critical to maintaining independence and autonomy to pursue further activity. One clinical expression of enteric neurodegeneration is constipation. However, the aetiology may be multifactorial as disturbances of epithelial, muscle or neural function may all result from neurodegeneration. There is evidence of loss of excitatory (e.g. cholinergic) enteric neurons and interstitial cells of Cajal, whereas inhibitory (including nitrergic) neurons appear unaffected. Understanding neurodegeneration in the enteric nervous system is key to developing treatments to reverse it. Neurotrophins have been shown to accelerate colonic transit and relieve constipation in the medium term; they are also implicated in maintenance programmes in adult enteric neurons through a role in antioxidant defence. However, their effects in ageing colon require further study. There is evidence that 5-HT(2) and 5-HT(4) mechanisms are involved in development, maintenance and survival of enteric neurons. Further research is needed to understand and potentially reverse enteric neurodegeneration.

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Section: Serotonergic Mechanisms In Maintenance and Survival Of Entermentioning

confidence: 99%

Enteric neurodegeneration in ageing

Camilleri

Cowen

Koch

2008

Neurogastroenterology Motil

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“…For example, serotonin has been described to modulate proinflammatory cytokines production in human monocytes via stimulation of different 5-HT receptor subtypes, particularly 5-HT3, 5-HT4 and 5-HT7 receptors [85] ( Figure 1C). Interestingly, deletion of 5-HT4 receptors in mice results in inflammatory response, slowed colonic motility, and behavioral abnormalities [86,87].…”

Section: Gastrointestinal Inflammation and Depressionmentioning

confidence: 99%

Role of Microbiota and Tryptophan Metabolites in the Remote Effect of Intestinal Inflammation on Brain and Depression

Waclawiková¹,

Aidy²

2018

Preprint

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The human gastrointestinal tract is inhabited by trillions of commensal bacteria collectively known as the gut microbiota. Our recognition of the significance of the complex interaction between the microbiota, and its host has grown dramatically over the past years. A balanced microbial community is a key regulator of the immune response, and metabolism of dietary components, which in turn, modulates several brain processes impacting mood and behavior. Consequently, it is likely that disruptions within the composition of the microbiota would remotely affect the mental state of the host. Here, we discuss how intestinal bacteria and their metabolites can orchestrate gut-associated neuroimmune mechanisms that influence mood and behavior leading to depression. In particular, we focus on microbiota-triggered gut inflammation and its implications in shifting the tryptophan metabolism towards kynurenine biosynthesis while disrupting the serotonergic signaling. We further investigate the gaps to be bridged in this exciting field of research in order to clarify our understanding of the multifaceted crosstalk in the microbiota-gut-brain interphase, bringing about a novel microbiota-targeted therapeutics for mental illnesses.

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“…The location of plasmalemmal 5‐HT 4 receptors in the bowel is restricted to the presynaptic sites at which their action has been demonstrated (internal pools of newly synthesized receptors in transport vesicles en route to the cell surface are not accessible to neurotransmitters or applied drugs) 67 . This location has recently been ascertained using in situ hybridization to identify the cells that express 5‐HT 4 receptors and selective antibodies to the receptor.…”

Section: ‐Ht4 Receptors Are Presynaptic Enhance Transmitter Releasementioning

confidence: 99%

“…Considerable recent insight has been obtained from studying the bowel of transgenic mice that lack 5‐HT 4 receptors 67 . Colonic motility is abnormally slow in these animals, confirming that the 5‐HT 4 receptor plays a critical role in the maintenance of normal colonic motility.…”

Section: Colonic Motility Is Abnormally Slow In Transgenic Mice That mentioning

confidence: 99%

Review article: serotonin receptors and transporters — roles in normal and abnormal gastrointestinal motility

Gershon

2004

Aliment Pharmacol Ther

459

377

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Summary The gut is the only organ that can display reflexes and integrative neuronal activity even when isolated from the central nervous system. This activity can be triggered by luminal stimuli that are detected by nerves via epithelial intermediation. Epithelial enterochromaffin cells act as sensory transducers that activate the mucosal processes of both intrinsic and extrinsic primary afferent neurones through their release of 5‐hydroxytryptamine (5‐HT). Intrinsic primary afferent neurones are present in both the submucosal and myenteric plexuses. Peristaltic and secretory reflexes are initiated by submucosal intrinsic primary afferent neurones, which are stimulated by 5‐HT acting at 5‐HT1P receptors. 5‐HT acting at 5‐HT4 receptors enhances the release of transmitters from their terminals and from other terminals in prokinetic reflex pathways. Signalling to the central nervous system is predominantly 5‐HT3 mediated, although serotonergic transmission within the enteric nervous system and the activation of myenteric intrinsic primary afferent neurones are also 5‐HT3 mediated. The differential distribution of 5‐HT receptor subtypes makes it possible to use 5‐HT3 antagonists and 5‐HT4 agonists to treat intestinal discomfort and motility. 5‐HT3 antagonists alleviate the nausea and vomiting associated with cancer chemotherapy and the discomfort from the bowel in irritable bowel syndrome; however, because 5‐HT‐mediated fast neurotransmission within the enteric nervous system and the stimulation of mucosal processes of myenteric intrinsic primary afferent neurones are 5‐HT3 mediated, 5‐HT3 antagonists tend to be constipating and should be used only when pre‐existing constipation is not a significant component of the problem to be treated. In contrast, 5‐HT4 agonists, such as tegaserod, are safe and effective in the treatment of irritable bowel syndrome with constipation and chronic constipation. They do not stimulate nociceptive extrinsic nerves nor initiate peristaltic and secretory reflexes. Instead, they rely on natural stimuli to activate reflexes, which they strengthen by enhancing the release of transmitters in prokinetic pathways. Finally, when all the signalling by 5‐HT is over, its action is terminated by uptake into enterocytes or neurones, which is mediated by the serotonin reuptake transporter. In inflammation, serotonergic signalling is specifically diminished in the mucosa. Transcripts encoding tryptophan hydroxylase‐1 and serotonin reuptake transporter are both markedly decreased. Successive potentiation of 5‐HT and/or desensitization of its receptor could account for the symptoms seen in diarrhoea‐predominant and constipation‐predominant irritable bowel syndrome, respectively. Symptoms associated with the down‐regulation of the serotonin reuptake transporter in the human mucosa in irritable bowel syndrome are similar to the symptoms associated with the knockout of the serotonin reuptake transporter in mice. The observation that molecular defects occur in the human gut in irritable bowel syndrome stre...

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Distribution of 5-Ht4 receptors in wild-type mice and analyses of intestinal motility in 5-Ht4 knockout mice

Cited by 18 publications

References 0 publications

Enteric neurodegeneration in ageing

Enteric neurodegeneration in ageing

Role of Microbiota and Tryptophan Metabolites in the Remote Effect of Intestinal Inflammation on Brain and Depression

Review article: serotonin receptors and transporters — roles in normal and abnormal gastrointestinal motility

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