Serotonin Augments Gut Pacemaker Activity via 5-HT3 Receptors

Liu, Hongnian; Ohya, Susumu; Nishizawa, Yuji; Sawamura, Kenta; Iino, Satoshi; Syed, Muhammad Ali; Goto, Kazunori; Imaizumi, Yuji; Nakayama, Shinsuke

doi:10.1371/journal.pone.0024928

Cited by 51 publications

(54 citation statements)

References 68 publications

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“…Serotonin (5-HT) produces its diverse effects through a variety of membrane-bound receptors in the central and peripheral system, and in the periphery such as the gut, cardiovascular system and blood4243. 5-HT receptors are well-documented in vertebrates, especially in humans44.…”

Section: Discussionmentioning

confidence: 99%

Identification and functional characterisation of 5-HT4 receptor in sea cucumber Apostichopus japonicus (Selenka)

Wang

Yang

Zhou

et al. 2017

Sci Rep

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Serotonin (5-HT) is an important neurotransmitter and neuromodulator that controls a variety of sensory and motor functions through 5-HT receptors (5-HTRs). The 5-HT4R subfamily is linked to Gs proteins, which activate adenylyl cyclases (ACs), and is involved in many responses in peripheral organs. In this study, the 5-HT4R from Apostichopus japonicus (Aj5-HT4R) was identified and characterised. The cloned full-length Aj5-HT4R cDNA is 1,544 bp long and contains an open reading frame 1,011 bp in length encoding 336 amino acid proteins. Bioinformatics analysis of the Aj5-HT4R protein indicated this receptor was a member of class A G protein coupled receptor (GPCR) family. Further experiments using Aj5-HT4R-transfected HEK293 cells demonstrated that treatment with 5-HT triggered a significant increase in intracellular cAMP level in a dose-dependent manner and induced a rapid internalisation of Aj5-HT4R fused with enhanced green fluorescent protein (Aj5-HT4R-EGFP) from the cell surface into the cytoplasm. In addition, the transcriptional profiles of Aj5-HT4R in aestivating A. japonicas and phosphofructokinase (AjPFK) in 5-HT administrated A. japonicus have been analysed by real-time PCR assays. Results have led to a basic understanding of Aj5-HT4R in A. japonicus, and provide a foundation for further exploration of the cell signaling and regulatory functions of this receptor.

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Section: Discussionmentioning

confidence: 99%

Identification and functional characterisation of 5-HT4 receptor in sea cucumber Apostichopus japonicus (Selenka)

Wang

Yang

Zhou

et al. 2017

Sci Rep

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“…IBS manifests as several different types, and some symptoms seen in patients with IBS-D are, to some extent, similar to the symptoms seen postoperatively in patients who undergo SPO for either rectal cancer or UC. Although the precise mechanism of IBS has not been identified, serotonin and 5-HT receptors in the gut may play a major role in the etiology of IBS 17. Hence, one of the most commonly used drugs for the treatment of IBS-D is reportedly 5-HT 3 antagonists 13.…”

Section: Discussionmentioning

confidence: 99%

Serotonin (5-HT3) receptor antagonists for the reduction of symptoms of low anterior resection syndrome

Itagaki¹,

Koda²,

Yamazaki³

et al. 2014

CEG

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PurposeSerotonin (5-hydroxytryptamine [5-HT])3 receptor antagonists are effective for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), in which exaggerated intestinal/colonic hypermotility is often observed. Recent studies have suggested that the motility disorder, especially spastic hypermotility, seen in the neorectum following sphincter-preserving operations for rectal cancer may be the basis of the postoperative defecatory malfunction seen in these patients. We investigated the efficacy of 5-HT3 receptor antagonists in patients suffering from severe low anterior resection syndrome.Patients and methodsA total of 25 male patients with complaints of uncontrollable urgency or fecal incontinence following sphincter-preserving operations were enrolled in this study. Defecatory status, assessed on the basis of incontinence score (0–20), urgency grade (0–3), and number of toilet visits per day, was evaluated using a questionnaire before and 1 month after the administration of the 5-HT3 antagonist ramosetron.ResultsAll the parameters assessed improved significantly after taking ramosetron for 1 month. The effect was more prominent in cases whose anastomotic line was lower, ie, inside the anal canal. Defecatory function was better in patients who commenced ramosetron therapy within 6 months postoperatively, as compared to those who were not prescribed ramosetron for more than 7 months postoperatively.ConclusionThese results suggest that 5-HT3 antagonists are effective for the treatment of low anterior resection syndrome, as in diarrhea-predominant irritable bowel syndrome. The improvement in symptoms is not merely time dependent, but it is related to treatment with 5-HT3 antagonists.

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“…Clearly, the role of 5-HT 3 receptors is important in normal physiology (Hansen and Witte, 2008; Liu et al ., 2011) and in irritable bowel syndrome (Spiller, 2008; Niesler, 2011) and their permanent inhibition would be undesirable. Perhaps palonosetron achieves the optimal period of time for 5-HT 3 receptor inhibition that prevents delayed emesis, but has consequences tolerable to normal physiological functions.…”

Section: Discussionmentioning

confidence: 99%

Prolonged inhibition of 5‐HT₃ receptors by palonosetron results from surface receptor inhibition rather than inducing receptor internalization

Hothersall

Moffat

Connolly

2013

British J Pharmacology

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Background and PurposeThe 5-HT3 receptor antagonist palonosetron is an important treatment for emesis and nausea during cancer therapy. Its clinical efficacy may result from its unique binding and clearance characteristics and receptor down-regulation mechanisms. We investigated the mechanisms by which palonosetron exerts its long-term inhibition of 5-HT3 receptors for a better understanding of its clinical efficacy.Experimental ApproachCell surface receptors (recombinantly expressed 5HT3A or 5HT3AB in COS-7 cells) were monitored using [3H]granisetron binding and ELISA after exposure to palonosetron. Receptor endocytosis was investigated using immunofluorescence microscopy.Key ResultsChronic exposure to palonosetron reduced the number of available cell surface [3H]granisetron binding sites. This down-regulation was not sensitive to either low temperature or pharmacological inhibitors of endocytosis (dynasore or nystatin) suggesting that internalization did not play a role. This was corroborated by our observation that there was no change in cell surface 5-HT3 receptor levels or increase in endocytic rate. Palonosetron exhibited slow dissociation from the receptor over many hours, with a significant proportion of binding sites being occupied for at least 4 days. Furthermore, our observations suggest that chronic receptor down-regulation involved interactions with an allosteric binding site.Conclusions and ImplicationsPalonosetron acts as a pseudo-irreversible antagonist causing prolonged inhibition of 5-HT3 receptors due to its very slow dissociation. In addition, an irreversible binding mode persists for at least 4 days. Allosteric receptor interactions appear to play a role in this phenomenon.

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Serotonin Augments Gut Pacemaker Activity via 5-HT3 Receptors

Cited by 51 publications

References 68 publications

Identification and functional characterisation of 5-HT4 receptor in sea cucumber Apostichopus japonicus (Selenka)

Identification and functional characterisation of 5-HT4 receptor in sea cucumber Apostichopus japonicus (Selenka)

Serotonin (5-HT3) receptor antagonists for the reduction of symptoms of low anterior resection syndrome

Prolonged inhibition of 5‐HT₃ receptors by palonosetron results from surface receptor inhibition rather than inducing receptor internalization

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Serotonin Augments Gut Pacemaker Activity via 5-HT3 Receptors

Cited by 51 publications

References 68 publications

Identification and functional characterisation of 5-HT4 receptor in sea cucumber Apostichopus japonicus (Selenka)

Identification and functional characterisation of 5-HT4 receptor in sea cucumber Apostichopus japonicus (Selenka)

Serotonin (5-HT3) receptor antagonists for the reduction of symptoms of low anterior resection syndrome

Prolonged inhibition of 5‐HT3 receptors by palonosetron results from surface receptor inhibition rather than inducing receptor internalization

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Prolonged inhibition of 5‐HT₃ receptors by palonosetron results from surface receptor inhibition rather than inducing receptor internalization