It is thought that oscillations of the intracellular Ca2+ concentration in ICC cells underlie gut pacemaker activity. Namely, periodic activation of Ca2+ -sensitive ion channels in the plasma membrane generates pacemaker potentials . Previously, we demonstrated that spontaneous electrical activity occurs in synchrony with i oscillations in ICC, and that coordinated actions of intracellular Ca2+ release channels and transmembrane Ca2+ influx pathways underlie ICC i oscillations . In the present study, we provide evidence that 5-HT regulates ICC pacemaker activity. We performed Ca2+ imaging and potential mapping of ICC pacemaker activity using fluorescent Ca2+ probes and microelectrode array , respectively, and found that 5-HT enhances both Ca2+ and electric activities of ICC via 5-HT3 receptors, which are nonselective TWS119 distributor cation channels permeable to Ca2+ . We also carried out RT-PCR and immunostaining to confirm the expression of 5-HT3 receptors in ICC. Our findings suggest that 5-HT modulation of ICC activity should also be considered for gut motility disorders, for example, irritable bowel syndrome with a prevalence of around 10% . Interestingly, this disease is known to be frequently complicated by psychiatric illness and mood disorders. ICC act as gut pacemaker cells. Moreover, fairly recent studies suggest that these cells also coordinate peristaltic movements through their network-forming structure . In the light of the important roles of ICC, any hormones and neurotransmitters that modulate ICC activity are considered to have a significant influence upon gut motility. The present finding that 5-HT augments ICC activity implies that this signalling molecule in particular plays a crucial role in regulating gut motility, because the gut contains a majority of 5-HT in the body . Five subunits are known to form the 5-HT3 receptor complex, and changes in the composition alter Ca2+ – permeability of this channel . In future studies, it would be of interest to elucidate the composition of 5-HT3A-E receptor subtypes and how 5-HT3 receptors are coupled to Ca2+ release channels in intracellular Ca2+ stores to generate pacemaker i activity. Polymorphism of these 5-HT3 receptor subunit genes seems likely to affect gut motility by modulating ICC as well as neuronal activities , and underlies some functional disorders .