title: A protein tyrosine kinase receptor, c-RET signaling pathway contributes to the enteric neurogenesis induced by a 5-HT4 receptor agonist at an anastomosis after transection of the gut in rodents.
abstract: We previously reported that a serotonin 4 (5-HT4) receptor agonist, mosapride citrate (MOS), increased the number of c-RET-positive cells and levels of c-RET mRNA in gel sponge implanted in the necks of rats. The 5-HT4 receptor is a G protein coupled receptor (GPCR) coupled to G protein Gs-cAMP cascades. We investigated the possibility that 5-HT4 receptor activation induced c-RET activation and/or PKA activation by elevating cAMP levels. Rodents were orally administered MOS by adding it to drinking water for 2 weeks after enteric nerve circuit insult via gut transection and anastomosis, together with the RET inhibitors withaferin A (WA) and RPI-1 or the PKA inhibitor H89. We then examined PGP9.5-positive cells in the newly formed granulation tissue at the anastomotic site. MOS significantly increased the number of new neurons, but not when co-administered with WA or RPI-1. Co-administration of H89 failed to alter MOS-induced increases in neurogenesis. In conclusion, the c-RET signaling pathway contributes to enteric neurogenesis facilitated by MOS, though the contribution of PKA activation seems unlikely.
authors: Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors: Kei
authors: K
authors: Goto
authors: Isao
authors: I
authors: Kawahara
authors: Hiroki
authors: H
authors: Kuniyasu
authors: Miyako
authors: M
authors: Takaki
mesh_terms: D000714:Anastomosis, Surgical; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D017615:Enteric Nervous System / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D005260:Female; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000601:surgery; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008959:Models, Neurological; D009025:Morpholines / Q000494:pharmacology; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D054358:Withanolides / Q000494:pharmacology
chemical_list: D001549:Benzamides; D007211:Indoles; D009025:Morpholines; C477359:RPI-1 compound; D058828:Serotonin 5-HT4 Receptor Agonists; D054358:Withanolides; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse; C062720:mosapride; C009684:withaferin A