The serotonin signaling system: from basic understanding to drug development for functional GI disorders

Gershon, Michael D.; Tack, Jan

doi:10.1053/j.gastro.2006.11.002

Cited by 1,563Gastrointestinal motility and disordersNeurotransmitter Receptor Influence on BehaviorReceptor Mechanisms and Signaling

The serotonin signaling system: from basic understanding to drug development for functional GI disorders

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Gershon, Michael D., Tack, Jan·2007·Gastroenterology

DOI 10.1053/j.gastro.2006.11.002

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Abstract

Serotonin is an important gastrointestinal signaling molecule. It is a paracrine messenger utilized by enterochromaffin (EC) cells, which function as sensory transducers. Serotonin activates intrinsic and extrinsic primary afferent neurons to, respectively, initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin is also a neurotransmitter utilized by a system of long descending myenteric interneurons. Serotonin is synthesized through the actions of 2 different tryptophan hydroxylases, TpH1 and TpH2, which are found, respectively, in EC cells and neurons. Serotonin is inactivated by the serotonin reuptake transporter (SERT)-mediated uptake into enterocytes or neurons. The presence of many serotonin receptor subtypes enables selective drugs to be designed to therapeutically modulate gastrointestinal motility, secretion, and sensation. Current examples include tegaserod, a 5-HT(4) partial agonist, which has been approved for treatment of irritable bowel syndrome (IBS) with constipation in women and for chronic constipation in men and women. The 5-HT(3) antagonists, granisetron and ondansetron, are useful in combating the nausea associated with cancer chemotherapy, and alosetron is employed in the treatment of IBS with diarrhea. Serotonergic signaling abnormalities have also been putatively implicated in the pathogenesis of functional bowel diseases. Other compounds, for which efficacy has not been rigorously established, but which may have value, include tricyclic antidepressants and serotonin selective reuptake inhibitors to combat IBS, and 5-HT(1) agonists, which enhance gastric accommodation, to treat functional dyspepsia. The initial success encountered with serotonergic agents holds promise for newer and more potent insights and therapies of brain-gut disorders.

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The GM regulates serotonin availability by signaling enterochromaffin cells to produce serotonin via TPH expression, and by altering SCFAs and BAs.
“The GM can further regulate serotonin availability by signaling enterochromaffin cells to produce serotonin via expression of tryptophan hydroxylase, and by altering levels of SCFAs and BAs which can influence serotonin production (46, 164, 221–223).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [221]
Enterochromaffin cells secrete serotonin and signaling peptides in response to various physiological and pathological luminal stimuli, such as microbial factors or bacterial toxins, as well as central stimuli.
“Enterochromaffin cells secrete serotonin and signaling peptides (for example, corticotropin-releasing hormone, cholecystokinin and somatostatin) in response to various physiological and pathological luminal stimuli,53-55 such as microbial factors or bacterial toxins,56-58 as well as central stimuli (see discussion above).31,32”
From Principles and clinical implications of the brain-gut-enteric microbiota axis (2009) · cites this paper as [54]

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Authors: Gershon, M. D., & Tack, J.
Affiliations: Columbia University Irving Medical Center (US)
ORCID: Gershon, Michael D.
Tack, Jan
Venue: Gastroenterology
Publisher: Elsevier BV
Published: 2007-01
Volume: 132
Issue: 1
Pages: 397-414
ISSN: 0016-5085 (ISSN-L)
DOI: 10.1053/j.gastro.2006.11.002
OpenAlex: W1969144895
Cited by: 1,563
References: 250
Citations by year: 2026: 74 · 2025: 93 · 2024: 90 · 2023: 91 · 2022: 98 · 2021: 107 · 2020: 109 · 2019: 81 · 2018: 79 · 2017: 88 · 2016: 76 · 2015: 72 · 2014: 72 · 2013: 70 · 2012: 59
FWCI: 13.53
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Gastroenterology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: serotonin signaling, enterochromaffin cells, tryptophan hydroxylase, serotonin transporter, serotonin receptors, 5-HT4 receptor agonist, tegaserod, 5-HT3 receptor antagonists, alosetron, irritable bowel syndrome, functional dyspepsia, functional gastrointestinal disorders, gastrointestinal motility, selective serotonin reuptake inhibitors, tricyclic antidepressants, gut-brain axis
MeSH terms: Animals, Gastrointestinal Diseases, Humans, Serotonin, Drug Design, Signal Transduction, Gastrointestinal Tract

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The serotonin signaling system: from basic understanding to drug development for functional GI disorders

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