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Review
. 2017;239:319-342.
doi: 10.1007/164_2016_103.

Serotonergic Mechanisms Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance

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Free PMC article
Review

Serotonergic Mechanisms Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance

Natalie Terry et al. Handb Exp Pharmacol. .
Free PMC article

Abstract

Serotonin (5-hydroxytryptamine; 5-HT) is best known as a neurotransmitter critical for central nervous system (CNS) development and function. 95% of the body's serotonin, however, is produced in the intestine where it has been increasingly recognized for its hormonal, autocrine, paracrine, and endocrine actions. This chapter provides the most current knowledge of the critical autocrine and paracrine roles of 5-HT in intestinal motility and inflammation as well as its function as a hormone in osteocyte homeostasis. Therapeutic applications in each of these areas are also discussed.

Keywords: Bone; Enteric nervous system; Intestinal inflammation; Intestine; Motility; Serotonin.

Figures

Fig. 1
Fig. 1
5-HT biosynthesis. L-tryptophan is taken up by enterochromaffin (EC) cells (purple) where it is converted by tryptophan hydroxylase 1 (TPH1) to 5-hydroxytryptophan (5-HTP). The enzyme L-amino acid decarboxylase (L-AAD) then produces 5-hydroxytryptophan (5-HT) which is released into the extracellular space and can either act locally in the intestine, via its receptors in the intestinal mucosa or intercalated dendrites of the submucosal and myenteric plexuses, or be taken up by platelets (red) via the serotonin transporter (SERT). Locally acting 5-HT will be taken up by the enterocytes, via SERT, where it is broken down by monoamine oxidase (MAO) and metabolized to 5-hydroxyindoleacetic acid (5-HIAA). The 5-HT taken up by platelets is either released at a distal site, where it can execute hormonal actions, or metabolized, as in the enterocytes, by MAO within the platelet, and later excreted by the kidneys
Fig. 2
Fig. 2
5-HT signals in an autocrine, paracrine, and endocrine fashion. (a) In the intestinal epithelium, mucosal 5-HT (orange diamonds) is produced by TPH1 in the enterochromaffin cells (dark purple) where, once secreted, it will signal in an autocrine or paracrine fashion, to itself or to neighboring enterocytes (green), respectively, via 5-HT receptors (pictured in red). Once 5-HT has perpetrated its actions it needs to be inactivated or receptor desensitization can occur. In order to undergo inactivation, mucosal 5-HT must be taken up by the serotonin reuptake transporter (SERT; blue spheres), located on intestinal epithelial cells, where, once intracellular, it can be broken down by monoamine oxidase. (b) 5-HT secreted into the intestine can also be taken up via SERT (blue sphere) in platelets to be transported in the bloodstream to distal sites for endocrine function. (c) In the enteric nervous system, 5-HT is produced by TPH2 in 2–3% of enteric neurons. 5-HT is released into the synapse and activates postsynaptic 5-HT receptors. It is then taken up by SERT in the presynaptic neuron for deactivation

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