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.

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Available from: Michael D Gershon, Apr 10, 2014
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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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    • "The serotonin 5-hydroxytryptamine 4(5-HT 4 ) receptor is a 43 member of the seven-transmembrane-spanning G protein-coupled 44 family of receptors (Restivo et al., 2008). It has been realized that 45 the activation of 5-HT 4 receptor plays an important modulatory 46 role in the function of several tissues including the central nervous 47 system (CNS), gastrointestinal tract (GI), adrenal gland, and urinary 48 bladder through which the neurotransmitter 5-HT 4 affects organ 49 function by signaling through receptors that present throughout 50 these systems (Gershon, 2004; Neal and Bornstein, 2006; 51 Costedio et al., 2007; Gershon and Tack, 2007). In the GI tract, 5- 52 HT 4 receptors are located on the terminals of myenteric neurons 53 and GI smooth muscle cells, whose activation stimulates smooth 54 muscle contraction and the peristaltic reflex and whose agonists 55 enhance large intestinal contractility by facilitating acetylcholine 56 release on cholinergic nerves and myenteric nerve plexus. "
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    ABSTRACT: Serotonin 5-hydroxytryptamine 4 (5-HT4) receptor agonists have been widely prescribed as a prokinetics drug for patients with gastro-esophageal reflux disease and functional dyspepsia. QX100626, one of the 5-HT4 receptor agonists, has been studied as a promising agent for this clinical use. The objective of the present study was to identify possible target organs of toxicity and propose a non-toxic dose of QX100626 for clinical usage. After single lethal dose oral and intravenous testing in rodents, some signs indicative of adverse CNS effects were observed. The minimum toxic dose of QX100626 for a single oral administration for dogs was 90.0 mg/kg b.w., and the severe toxic dose was more than 300 mg/kg b.w. The No Observed Adverse Effect Level (NOAEL) of QX100626 by daily oral administration for rats and dogs was 20 mg/kg and 10 mg/kg, respectively, whereas the minimum toxic dosages were 67 and 30 mg/kg, respectively. All of the adverse effects suggested that kidney, digestive tract, as well as nervous, hematological, and respiratory systems might be the target organs of toxicity for humans induced by QX100626. The compound could be a safe alternative to other existing prokinetic agents for the treatment of functional bowel disorders.
    Regulatory Toxicology and Pharmacology 10/2014; 70(1). DOI:10.1016/j.yrtph.2014.07.024 · 2.03 Impact Factor
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