Serotonin Augments Gut Pacemaker Activity via 5-HT3 Receptors

Hong-Nian Liu,Shinsuke Nakayama,Kenta Sawamura,Mohsin Md Syed,Kazunori Goto,Satoshi Iino,Susumu Ohya,Yuji Imaizumi,Yuji Nishizawa,Markus M. Heimesaat

doi:10.1371/journal.pone.0024928

Hong-Nian Liu, Shinsuke Nakayama + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0024928

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Abstract

Serotonin (5-hydroxytryptamine: 5-HT) affects numerous functions in the gut, such as secretion, muscle contraction, and enteric nervous activity, and therefore to clarify details of 5-HT's actions leads to good therapeutic strategies for gut functional disorders. The role of interstitial cells of Cajal (ICC), as pacemaker cells, has been recognised relatively recently. We thus investigated 5-HT actions on ICC pacemaker activity. Muscle preparations with myenteric plexus were isolated from the murine ileum. Spatio-temporal measurements of intracellular Ca2+ and electric activities in ICC were performed by employing fluorescent Ca2+ imaging and microelectrode array (MEA) systems, respectively. Dihydropyridine (DHP) Ca2+ antagonists and tetrodotoxin (TTX) were applied to suppress smooth muscle and nerve activities, respectively. 5-HT significantly enhanced spontaneous Ca2+ oscillations that are considered to underlie electric pacemaker activity in ICC. LY-278584, a 5-HT3 receptor antagonist suppressed spontaneous Ca2+ activity in ICC, while 2-methylserotonin (2-Me-5-HT), a 5-HT3 receptor agonist, restored it. GR113808, a selective antagonist for 5-HT4, and O-methyl-5-HT (O-Me-5-HT), a non-selective 5-HT receptor agonist lacking affinity for 5-HT3 receptors, had little effect on ICC Ca2+ activity. In MEA measurements of ICC electric activity, 5-HT and 2-Me-5-HT caused excitatory effects. RT-PCR and immunostaining confirmed expression of 5-HT3 receptors in ICC. The results indicate that 5-HT augments ICC pacemaker activity via 5-HT3 receptors. ICC appear to be a promising target for treatment of functional motility disorders of the gut, for example, irritable bowel syndrome.

Highlights

Special interstitial cells with abundant c-Kit receptors on their surface are distributed throughout the gastrointestinal tract
Since enteric neurones and smooth muscle cells express various 5-HT receptors depending upon cell type and location of the cell, and their functions are critically affected by this signalling molecule [11,12], 5-HT receptors are key targets in pharmacological interventions of gut functional disorders, as well as psychiatric disorders of the brain
In the light of the important roles of interstitial cells of Cajal (ICC), any hormones and neurotransmitters that modulate ICC activity are considered to have a significant influence upon gut motility

Summary

Introduction

Special interstitial cells with abundant c-Kit receptors on their surface are distributed throughout the gastrointestinal tract. Since enteric neurones and smooth muscle cells express various 5-HT receptors depending upon cell type and location of the cell, and their functions are critically affected by this signalling molecule [11,12], 5-HT receptors are key targets in pharmacological interventions of gut functional disorders, as well as psychiatric disorders of the brain. Our findings suggest that 5-HT modulation of ICC activity should be considered for gut motility disorders, for example, irritable bowel syndrome with a prevalence of around 10% [18]. This disease is known to be frequently complicated by psychiatric illness and mood disorders

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