The Serotonin Signaling System: From Basic Understanding To Drug Development for Functional GI Disorders

Department of Pathology & Cell Biology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
Gastroenterology (Impact Factor: 16.72). 02/2007; 132(1):397-414. DOI: 10.1053/j.gastro.2006.11.002
Source: PubMed


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.


Available from: Michael D Gershon, Apr 10, 2014
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    • "5-HT 3 RECEPTORS AND VAGAL SENSORY FUNCTIONS 5-HT is an important neurotransmitter in several GI functions, and >90% of the total body 5-HT is contained with the GI tract, either within specialized enteroendocrine cells, termed enterochromaffin (EC) cells or within neurons. Excellent recent reviews have provided in depth coverage of the role of 5-HT within the GI tract (Gershon and Tack, 2007; Mawe and Hoffman, 2013); this review, therefore, will concentrate on the role of 5- HT 3 receptors in gut-brain and brain-gut signaling outside the GI tract itself. Electrophysiological studies have demonstrated functionally active 5-HT 3 receptors on vagal afferent neurons and fibers (Leal-Cardoso et al., 1993; Hillsley et al., 1998; Kreis et al., 2002; Moore et al., 2002; Lacolley et al., 2006a; Babic et al., 2012) and activation of 5-HT 3 receptors induces a short latency, transient increase in firing rate of vagal afferents (Hillsley and Grundy, 1998; Hillsley et al., 1998) or a brief, rapid inward current (or membrane depolarization), in isolated neurons (Leal- Cardoso et al., 1993; Peters et al., 1993; Babic et al., 2012) consistent with its function as a ligand-gated cation channel (Derkach et al., 1989). "
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    ABSTRACT: Vagal neurocircuits are vitally important in the co-ordination and modulation of GI reflexes and homeostatic functions. 5-hydroxytryptamine (5-HT; serotonin) is critically important in the regulation of several of these autonomic gastrointestinal (GI) functions including motility, secretion and visceral sensitivity. While several 5-HT receptors are involved in these physiological responses, the ligand-gated 5-HT3 receptor appears intimately involved in gut-brain signaling, particularly via the afferent (sensory) vagus nerve. 5-HT is released from enterochromaffin cells in response to mechanical or chemical stimulation of the GI tract which leads to activation of 5-HT3 receptors on the terminals of vagal afferents. 5-HT3 receptors are also present on the soma of vagal afferent neurons, including GI vagal afferent neurons, where they can be activated by circulating 5-HT. The central terminals of vagal afferents also exhibit 5-HT3 receptors that function to increase glutamatergic synaptic transmission to second order neurons of the nucleus tractus solitarius within the brainstem. While activation of central brainstem 5-HT3 receptors modulates visceral functions, it is still unclear whether central vagal neurons, i.e., nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) neurons themselves also display functional 5-HT3 receptors. Thus, activation of 5-HT3 receptors may modulate the excitability and activity of gastrointestinal vagal afferents at multiple sites and may be involved in several physiological and pathophysiological conditions, including distention- and chemical-evoked vagal reflexes, nausea, and vomiting, as well as visceral hypersensitivity.
    Frontiers in Neuroscience 10/2015; 9. DOI:10.3389/fnins.2015.00413 · 3.66 Impact Factor
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    • "5-HT (serotonin) is one of the most important signalling molecules affecting gastrointestinal (GI) function due to its many contributions to physiological and pathophysiological conditions through its seven receptor subtypes and reuptake transporters (Gershon and Tack, 2007). More than 98% of 5-HT in humans is synthesized by enterochromaffin (EC) cells by the rate-limiting enzyme tryptophan hydroxylase (TPH)-1, followed by L-amino acid decarboxylase, whereas the remaining 2% is produced in CNS by TPH-2. "
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    ABSTRACT: The bioactive monoamine 5-hydroxytryptamine (5-HT), implicated in the pathogenesis of functional gastrointestinal disorders, is abundantly synthesized and stored in rat proximal colonic mucosa and released to the gut lumen and to the subepithelial space. Despite much data regarding its expression and function, the effects of luminal 5-HT on colonic anion secretion have not been fully investigated. We measured short-circuit current (Isc ) as an indicator of ion transport in mucosa-submucosa or mucosa-only preparations of rat proximal colon. Luminal 5-HT gradually increased the amplitude and sustained the elevation of Isc . Luminal 5-HT-evoked ΔIsc was acetazolamide-sensitive and HCO3 (-) -dependent, consistent with cytosolic carbonic anhydrase-dependent electrogenic HCO3 (-) secretion, while not affected by tetrodotoxin (TTX), atropine or indomethacin. Pretreatment with the selective 5-HT4 antagonist GR113808, but not antagonists for 5-HT3 , 5-HT6 , or 5-HT7 , inhibited luminal 5-HT-evoked ΔIsc . Furthermore, luminal cisapride and tegaserod increased Isc to the same extent as did 5-HT in the presence of indomethacin and TTX. Removal of the submucosa or pretreatment with nitric oxide synthase (NOS) inhibitors enhanced luminal 5-HT-evoked ΔIsc , suggesting that NO synthesized in the submucosa suppresses mucosal anion secretion. NOS1 and NOS2 were immunostained in the submucosal neurons and glial cells, respectively. Luminal 5-HT-evoked HCO3 (-) secretion was confirmed in vivo, inhibited by co-perfusion of GR113808, but not by ondansetron. We conclude that a novel apical 5-HT4 -mediated HCO3 (-) secretory pathway and an NO-dependent inhibitory mechanism are present in the proximal colon. Luminal 5-HT-evoked HCO3 (-) secretion may be important for the maintenance of mucosal integrity by regulating luminal pH. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13216 · 4.84 Impact Factor
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    • "5-HT is an indolamine [3-(b-aminoethyl)-5-hydroxyindole] (Kim & Camilleri 2000) that functions as a neurotransmitter , both in the gut and in the brain, and as a paracrine messenger in the gut (Gershon & Tack 2007), as well as a hormone in the periphery (Gershon 2013). The total amount of 5-HT found in the human body is derived from only 5% of the essential amino acid tryptophan (Tyce 1990). "
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    ABSTRACT: Serotonin or 5- hydoxytryptamine (5-HT) is a neurotransmitter and hormone that contributes to the regulation of various physiological functions by its actions in the central nervous system (CNS), and in the respective organ systems. Peripheral 5-HT is predominantly produced by enterochromaffin (EC) cells of the gastrointestinal (GI) tract. These gut resident cells produce much more 5-HT than all neuronal and other sources combined, establishing EC cells as the main source of this biogenic amine in the human body. Peripheral 5-HT is also a potent immune modulator and affects various immune cells through its receptors and via the recently identified process of serotonylation. Alterations in 5-HT signalling have been described in inflammatory conditions of the gut, such inflammatory bowel disease. The association between 5-HT and inflammation, however, is not limited to the gut; as changes in 5-HT levels have also been reported in patients with allergic airway inflammation and rheumatoid arthritis. Based on searches for terms such as “5-HT,” “EC cell,” “immune cells,” and “inflammation” in pubmed. gov as well as by utilizing pertinent reviews, the current review aims to provide an update on the role of 5-HT in biological functions with a particular focus on immune activation and inflammation.This article is protected by copyright. All rights reserved.
    Acta Physiologica 11/2014; 213(3). DOI:10.1111/apha.12430 · 4.38 Impact Factor
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