1. Colonic Motility Is Improved by the Activation of 5-HT 2B Receptors on Interstitial Cells of Cajal in Diabetic Mice.
- Author
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Jin B, Ha SE, Wei L, Singh R, Zogg H, Clemmensen B, Heredia DJ, Gould TW, Sanders KM, and Ro S
- Subjects
- Animals, Calcium Signaling, Colon metabolism, Colon physiopathology, Constipation etiology, Constipation metabolism, Constipation physiopathology, Diabetes Complications metabolism, Diabetes Complications physiopathology, Disease Models, Animal, Female, Genes, Reporter, Interstitial Cells of Cajal metabolism, Male, Mice, Inbred C57BL, Mice, Transgenic, Ovariectomy, Proto-Oncogene Proteins c-kit genetics, Proto-Oncogene Proteins c-kit metabolism, Receptor, Serotonin, 5-HT2B metabolism, Serotonin metabolism, Tryptophan Hydroxylase genetics, Tryptophan Hydroxylase metabolism, Mice, Colon drug effects, Constipation prevention & control, Diabetes Complications prevention & control, Gastrointestinal Motility drug effects, Indoles pharmacology, Interstitial Cells of Cajal drug effects, Myoelectric Complex, Migrating drug effects, Receptor, Serotonin, 5-HT2B drug effects, Serotonin 5-HT2 Receptor Agonists pharmacology, Thiophenes pharmacology
- Abstract
Background & Aims: Constipation is commonly associated with diabetes. Serotonin (5-HT), produced predominantly by enterochromaffin (EC) cells via tryptophan hydroxylase 1 (TPH1), is a key modulator of gastrointestinal (GI) motility. However, the role of serotonergic signaling in constipation associated with diabetes is unknown., Methods: We generated EC cell reporter Tph1-tdTom, EC cell-depleted Tph1-DTA, combined Tph1-tdTom-DTA, and interstitial cell of Cajal (ICC)-specific Kit-GCaMP6 mice. Male mice and surgically ovariectomized female mice were fed a high-fat high-sucrose diet to induce diabetes. The effect of serotonergic signaling on GI motility was studied by examining 5-HT receptor expression in the colon and in vivo GI transit, colonic migrating motor complexes (CMMCs), and calcium imaging in mice treated with either a 5-HT
2B receptor (HTR2B) antagonist or agonist., Results: Colonic transit was delayed in males with diabetes, although colonic Tph1+ cell density and 5-HT levels were increased. Colonic transit was not further reduced in diabetic mice by EC cell depletion. The HTR2B protein, predominantly expressed by colonic ICCs, was markedly decreased in the colonic muscles of males and ovariectomized females with diabetes. Ca2+ activity in colonic ICCs was decreased in diabetic males. Treatment with an HTR2B antagonist impaired CMMCs and colonic motility in healthy males, whereas treatment with an HTR2B agonist improved CMMCs and colonic motility in males with diabetes. Colonic transit in ovariectomized females with diabetes was also improved significantly by the HTR2B agonist treatment., Conclusions: Impaired colonic motility in mice with diabetes was improved by enhancing HTR2B signaling. The HTR2B agonist may provide therapeutic benefits for constipation associated with diabetes., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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