These molecules may access ICC to activate in parallel. The present finding on augmentation of ICC activity via 5-HT3 receptors implies pharmacological interventions on gut motility disorders. For example, irritable bowel syndrome, classified into two types, i.e. diarrhoea- and constipation-dominant IBS , is known to involve 5-HT-related mechanisms along with infectious and inflammatory changes. Excess 5-HT due to impairment of reuptake transport is ascribed to some populations of d-IBS . Also, antineoplastic drugs, e.g. cisplatinum, stimulate 5-HT release . In such cases, it is rational to suppress ICC pacemaker activity in addition to nervous activities by blocking 5-HT3 receptors. It is speculated that stimulation of 5- HT3 receptors in enteric neurons and ICC synergically facilitates gut contractility and afferent neural activity toward the brain. Thereby, 5-HT3 receptors in the gut may contribute to the gutbrain axis. As seen in murine ileal ICC, we have also observed that 5-HT3 receptor agonists potentiate, while antagonists suppress both Ca2+ and electric pacemaker activities in the murine stomach in preliminary experiments. Although extensive studies are required in model animals and humans, 5-HT is likely to enhance ICC pacemaker activity throughout the gastrointestinal tract. Similar regulatory mechanisms may underlie other peripheral spontaneous activities. Evidence is being accumulated that Ruxolitinib JAK inhibitor ICClike interstitial cells ubiquitously exist in many organs and tissues that are effectors of the autonomic nervous system, such as the ureter, urinary bladder, urethra, uterus, lymph ducts, veins, etc, suggesting their possible contribution to spontaneous activity . Also, in some ICC-like cells, spontaneous i and electric activities have already been demonstrated. In the light of regulatory mechanisms of ICC and ICC-like cells, investigating functional disorders related to a wide range of peripheral spontaneous rhythmicity, e.g. irritable bladder, is merited. In summary, the present study has shown 5-HT augmentation of ICC pacemaker activity via 5-HT3 receptors. Since 5-HT3 receptors are Ca2+ -permeable nonselective cation channels, this effect on ICC activity is presumably through enhancement of Ca2+ influx from the extracellular space, through itself and simultaneous activation of voltage-gated Ca2+ -permeable channels.