Metabotropic 5‐HT receptor‐mediated effects in the human submucous plexus

Background Serotonin (5‐HT) is an important mediator in the gastrointestinal tract, acting on different neuronal 5‐HT receptors. The ionotropic 5‐HT3 receptor mediates immediate but transient spike discharge in human enteric neurons. We studied the role of the metabotropic 5‐HT1P, 5‐HT4, and 5‐HT7 r...

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Published in:	Neurogastroenterology and motility Vol. 34; no. 10; pp. e14380 - n/a
Main Authors:	Annaházi, Anita, Berger, Thomas Erwin, Demir, Ihsan Ekin, Zeller, Florian, Müller, Michael, Anneser, Markus, Skerra, Arne, Michel, Klaus, Schemann, Michael
Format:	Journal Article
Language:	English
Published:	England Wiley Subscription Services, Inc 01-10-2022
Subjects:	5‐HT1p 5‐HT4 5‐HT7 Agonists Enteric nervous system Gastrointestinal tract human submucous neurons Large intestine Metabotropic receptors metabotropic serotonin receptors Neuroimaging Neurons Serotonin Submucosal plexus 5-HT4 metabotropic serotonin receptors 5-HT7 5-HT1p human submucous neurons
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Summary:	Background Serotonin (5‐HT) is an important mediator in the gastrointestinal tract, acting on different neuronal 5‐HT receptors. The ionotropic 5‐HT3 receptor mediates immediate but transient spike discharge in human enteric neurons. We studied the role of the metabotropic 5‐HT1P, 5‐HT4, and 5‐HT7 receptors to activate human submucous neurons. Methods Neuroimaging using the voltage sensitive dye Di‐8‐ANEPPS was performed in submucous plexus preparations from human surgical specimens of the small and large intestine. We synthesized a new, stable 5‐HT1P agonist, 5‐benzyloxyhydrazonoindalpine (5‐BOHIP). Key Results 5‐HT evoked a fast and late‐onset spike discharge in enteric neurons. The fast component was blocked by the 5‐HT3 receptor antagonist cilansetron, while the remaining sustained response was significantly reduced by the 5‐HT1P receptor antagonist 5‐hydroxytryptophanyl‐5‐hydroxytryptophan amide (5‐HTP‐DP). The newly synthesized 5‐HT1P agonist 5‐BOHIP induced a slowly developing, long‐lasting activation of submucous neurons, which was blocked by 5‐HTP‐DP. We could not demonstrate any 5‐HT7 receptor‐induced spike discharge based on the lack of response to 5‐carboxamidotryptamine. Similarly, the 5‐HT4 agonists 5‐methoxytryptamine and prucalopride evoked no immediate or late‐onset spike discharge. Conclusions & Inferences Our work demonstrated for the first time the presence of functional 5‐HT1P receptors on human submucous neurons. Furthermore, we found no evidence for a role of 5‐HT4 or 5‐HT7 receptors in the postsynaptic activation of human submucous neurons by 5‐HT. The activation of human submucous neurons evoked by serotonin (5‐HT) has two components: the fast response is mediated by the ionotropic 5‐HT3 receptor while in the late onset response the 5‐HT1P, but not 5‐HT4 and 5‐HT7 receptors are involved. In this study, a new, stable 5‐HT1P agonist, 5‐benzyloxyhydrazonoindalpine (5‐BOHIP), was discovered.
Bibliography:	Funding information Supported by DFG (AN 1526/2‐1). ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1350-1925 1365-2982
DOI:	10.1111/nmo.14380