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

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-HT_2B 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-HT_2B receptor mRNA was detected by reverse transcriptase–polymerase chain reaction (RT-PCR) in jejunal muscle, whereas 5-HT_1A, 5-HT_1D, and 5-HT_2C receptor mRNAs were not. 5-HT_2B 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-HT_2B receptor antagonist, SB204741, inhibited the effect of 5-HT. The 5-HT_2B 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-HT_2B receptors are expressed on ICC. Exogenous 5-HT regulates ICC numbers through 5-HT_2B receptors in part by increasing ICC proliferation. The 5-HT_2B receptor may serve as a novel pathway to regulate ICC numbers. [Copyright &y& Elsevier]