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: 13.93). 02/2007; 132(1):397-414. DOI: 10.1053/j.gastro.2006.11.002
Source: PubMed

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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Available from: Michael D Gershon, Apr 10, 2014
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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 · 4.25 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 · 2.14 Impact Factor
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    • "Serotonin in mammals functions as an autacoid in the periphery (Gershon and Tack, 2007; Lesurtel and Clavien, 2012) and as a neurotransmitter in the central nervous system (CNS) (Invernizzi, 2007; Lesch et al., 2012; Lucki, 1998). In humans dysfunction of the serotonergic system is thought to be implicated in the development of many psychiatric disorders. "
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    ABSTRACT: Polymorphisms in the TPH2 gene coding for the serotonin synthesising enzyme in the brain are considered as risk factors associated with depression and anxiety in humans. However, whether a certain variation in the TPH2 gene leads to decreased brain serotonin production and development of psychological abnormalities remains unresolved. We generated a new mouse model, carrying one Tph2-null allele and one Tph21473G-allele, coding for a hypoactive form of the enzyme. We tested these mice along with C57BL/6 mice (Tph2(C/C)), congenic C57BL/6 mice homozygous for the Tph21473G-allele (Tph2(G/G)), and heterozygous Tph2-deficient mice (Tph2(C/-)) for anxiety- and depression-like behavior, and evaluated brain serotonin metabolism and 5-HT1AR signaling by high-performance liquid chromatography and quantitative autoradiography, respectively. Progressive reduction in TPH2 activity had no effect on emotional behavior, and only slightly affected brain serotonin levels. However, serotonin degradation rate was drastically decreased in mice with reduced TPH2 activity, thereby compensating for the lowered rate of serotonin production in these mice. In addition, the hypothermic response to the 5-HT1AR agonist, 8-OH-DPAT, was attenuated in mice with reduced serotonin production. In contrast, 5-HT1A autoreceptor density and G-protein coupling was not changed in mice with gradual decrease in central serotonin. Taken together, these data suggest that in conditions of reduced serotonin production lowered serotonin degradation rate contributes to the maintenance of brain serotonin at levels sufficient for adequate behavior responses. These findings reveal that decreased TPH2 activity cannot be considered a reliable predisposition factor for impaired emotional behavior.
    Neuropharmacology 05/2014; 85. DOI:10.1016/j.neuropharm.2014.05.015 · 4.82 Impact Factor
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