In the present study, Y25130 (a 5-HT3 receptor antagonist) and RS39604 (a 5-HT4 receptor antagonist) blocked SCRT-induced membrane depolarizations, whereas SB269970 (a 5-HT7 receptor antagonist) Dorsomorphin did not. Thus, it appears that SCRT modulates pacemaker potentials through 5-HT3 and 5-HT4 receptors-mediated pathways in the ICCs of mouse small intestine (Figure 2).In this study, ICCs generated pacemaker potentials in mouse small intestine. SCRT produced membrane depolarization in current clamp mode. Y25130 (a 5-HT3 receptor antagonist) and RS39604 (a 5-HT4 receptor antagonist) blocked MPF-induced membrane depolarizations, whereas SB269970 (a 5-HT7 receptor antagonist) did not. When GDP-��-S (1mM) was in the pipette solution, SCRT did not induce the membrane depolarizations.

Also, SCRT increased intracellular Ca2+ concentrations. To examined whether or not MAPKs are involved in the effects induced by SCRT, we used PD98059 (a p42/44 MAPK inhibitor), SB203580 (a p38 MAPK inhibitor), or c-jun NH2-terminal kinase (JNK) II inhibitor. In the presence of PD98059 (10��M), SCRT did not produce membrane depolarizations. In addition, SB203580 and JNK II inhibitor blocked the depolarizations by SCRT in pacemaker potentials. Furthermore, the membrane depolarizations by SCRT were inhibited not by U-73122, an active phospholipase C (PLC) inhibitors but by U-73343, an inactive PLC inhibitors. These results suggest that SCRT might affect GI motility by the modulation of pacemaker activity through MAPKs and PLC pathways in the ICCs.We think that SCRT activates PLC pathway (Figure 5) and increases intracellular Ca2+ levels (Figure 4).

Intracellular Ca2+ increases induce the membrane depolarizations on ICCs and then make ICCs contractions (Figure 7). However, the exact mechanisms of membrane depolarizations on ICCs should be investigated in future.Figure 7Hypothetical schematic signaling pathway of SCRT-induced membrane depolarizations on ICCs. SCRT-induced membrane depolarization seems to be mediated by 5-HT3 and/or 5-HT4 receptor, coupled to G protein, resulting in the activation of PLC pathway, which …The signaling pathways of MAPKs play important roles in the mediation of cellular responses, including visceral smooth muscle contraction. Three principal MAPKs are expressed in various tissues (p42/44, JNK, and p38 MAPK) [31].

Furthermore, it has been demonstrated 5-HT7 receptors GSK-3 activate MAP kinase in hippocampal neurons [32] and that 5-HT induces cyclooxygenase (COX)-2 by activating MAPK in vascular smooth muscle cells [33], which show that 5-HT can regulate the MAPK system. In the present study, we do not know whether this SCRT has a role of 5-HT or not. However, in this study, an inhibitor of p42/44 and p38 and a JNK II inhibitor inhibited the effect of SCRT, which suggests that p38, p42/44, and JNK MAPK are involved in the modulation of pacemaker potentials by SCRT.