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 (5HT) 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-polyrnerase 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 (I mu mol/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.