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The Shaggy Dog Story of Enteric Signaling: Serotonin, a Molecular Megillah

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The Enteric Nervous System II

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1383))

Abstract

Historically and quantitatively, the enteric site of serotonin (5-HT) storage has primacy over those of any other organ. 5-HT, by the name of “enteramine”, was first discovered in the bowel, and the gut produces most of the body’s 5-HT. Not only does the bowel secrete 5-HT prodigiously but it also expresses a kaleidoscopic abundance of 5-HT receptors. The larger of two enteric 5-HT stores is mucosal, biosynthetically dependent upon tryptophan hydroxylase1 (TPH1), and located in EC cells. Mechanical stimuli, nutrients, luminal bacteria, and neurotransmitters such as acetylcholine and norepinephrine are all able to stimulate EC cells. Paracrine actions of 5-HT allow the mucosa to signal to neurons to initiate peristaltic and secretory reflexes as well as to inflammatory cells to promote intestinal inflammation. Endocrine effects of 5-HT allow EC cells to influence distant organs, including bone, liver, and endocrine pancreas. The smaller enteric 5-HT store is biosynthetically dependent upon TPH2 and is located within a small subset of myenteric neurons. 5-HT is responsible for slow excitatory neurotransmission manifested primarily in type II/AH neurons. Importantly, neuronal 5-HT also promotes enteric nervous system (ENS) neurogenesis, both pre- and postnatally, through 5-HT2B and especially 5-HT4 receptors. The early birth of serotonergic neurons allows these cells to function as sculptors of the mature ENS. The inactivation of secreted 5-HT depends on transmembrane transport mediated by a serotonin transporter (SERT; SLC6A4). The importance of SERT in control of 5-HT’s function means that pharmacological inhibition of SERT, as well as gain- or loss-of-function mutations in SLC6A4, can exert profound effects on development and function of the ENS. Extra-enteric, TPH1-derived 5-HT from yolk sac and placenta promotes neurogenesis before enteric neurons synthesize 5-HT and contribute to ENS patterning. The impressive multi-functional nature of enteric 5-HT has made the precise identification of individual physiological roles difficult and sometimes controversial.

The authors’ work discussed in this chapter has been supported by grant number NS15547 of the National Institutes of Health of the US Public Health Service

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Authors and Affiliations

  1. Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA

    Michael D. Gershon

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  1. Michael D. Gershon
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Correspondence to Michael D. Gershon .

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Editors and Affiliations

  1. College of Medicine & Public Health Flinders Medical Centre, Adelaide, SA, Australia

    Nick J. Spencer

  2. College of Medicine & Public Health Flinders Medical Centre, Adelaide, SA, Australia

    Marcello Costa

  3. South Australian Health & Medical Research Institute, Adelaide, SA, Australia

    Stuart M. Brierley

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Gershon, M.D. (2022). The Shaggy Dog Story of Enteric Signaling: Serotonin, a Molecular Megillah. In: Spencer, N.J., Costa, M., Brierley, S.M. (eds) The Enteric Nervous System II. Advances in Experimental Medicine and Biology, vol 1383. Springer, Cham. https://doi.org/10.1007/978-3-031-05843-1_28

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