Exogenous Serotonin Regulates Proliferation of Interstitial Cells of Cajal in Mouse Jejunum Through 5-HT2B Receptors

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 133; no. 3; pp. 897 - 906
• Main Authors: Wouters, Mira M, Gibbons, Simon J, Roeder, Jaime L, Distad, Marne, Ou, Yijun, Strege, Peter R, Szurszewski, Joseph H, Farrugia, Gianrico
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2007
• Subjects: Animals; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Survival - physiology; Coculture Techniques; Gastroenterology and Hepatology; Indoles - pharmacology; Jejunum - cytology; Jejunum - drug effects; Jejunum - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Receptor, Serotonin, 5-HT2B - genetics; Receptor, Serotonin, 5-HT2B - metabolism; Ritanserin - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Serotonin - pharmacology; Serotonin 5-HT2 Receptor Agonists; Serotonin Agents - pharmacology; Serotonin Antagonists - pharmacology; Thiophenes - pharmacology; Urea - analogs & derivatives; Urea - pharmacology; RT; reverse transcriptase; ICC; 5-HT; RT-qPCR; interstitial cells of Cajal; PCR; polymerase chain reaction; real-time quantitative PCR; 5-hydroxytryptamine, serotonin
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2007.06.017

Background & Aims: Interstitial cells of Cajal (ICC) are required for normal gastrointestinal motility. Loss of ICC is associated with several motility disorders. The mechanisms modulating ICC survival and proliferation are poorly understood. This study aimed to establish whether 5-hydroxytryptamine (5-HT) plays a role in regulating ICC proliferation. Methods: Expression of 5-HT receptor mRNA was investigated in muscle strips, in purified populations of ICC, and in identified single cells. The effect of 5-HT2B receptor ligands on ICC numbers was studied in primary cell cultures. Proliferation of ICC was determined by counting Ki67-positive cells in culture. Results: Of the 5-HT receptors known to be involved in proliferation, 5-HT2B receptor mRNA was detected by reverse transcriptase–polymerase chain reaction (RT-PCR) in jejunal muscle, whereas 5-HT1A , 5-HT1D , and 5-HT2C receptor mRNAs were not. 5-HT2B receptor mRNA was found in single ICC and cells purified by flow cytometry. Exogenous 5-HT (1 μmol/L) increased (66% ± 9%, P < .005) ICC numbers in culture. The 5-HT2 receptor antagonist, ritanserin, and the 5-HT2B receptor antagonist, SB204741, inhibited the effect of 5-HT. The 5-HT2B receptor agonist BW 723C86 induced a concentration-dependent increase in ICC number (50% ± 6% at 50 nM, P < .04) and increased ICC proliferation (25% ± 3% vs 19 ± 1% in controls, P < .03). Conclusions: These studies establish that 5-HT2B receptors are expressed on ICC. Exogenous 5-HT regulates ICC numbers through 5-HT2B receptors in part by increasing ICC proliferation. The 5-HT2B receptor may serve as a novel pathway to regulate ICC numbers.