Recent advances in understanding the role of serotonin in gastrointestinal motility and functional bowel disorders

5-Hydroxytryptamine (5-HT, serotonin) is an important signalling molecule in the gastrointestinal tract. 5-Hydroxytryptamine is contained in a population of myenteric neurons whose axons project in an oral to anal direction. 5-Hydroxytryptamine is an excitatory neurotransmitter in the myenteric plexus where it mediates fast and slow excitatory postsynaptic potentials. These synaptic responses participate in the activity of neural circuits that control propulsive motility patterns in the small and large intestine. 5-Hydroxytryptamine is also contained in and released from enterochromaffin (EC) cells in the mucosal layer of the small and large intestine. Enterochromaffin cells function as mechanoand chemosensors that respond to luminal stimuli by releasing 5-HT from their basolateral surface. 5-HT released from EC cells then acts at several 5-HT receptor subtypes localized to the nerve endings of intrinsic and extrinsic primary afferent neurons. 5-Hydroxytryptamine-induced excitation of the mucosal endings of intrinsic primary afferent neurons initiates motor, secretomotor, and vasomotor reflexes mediated by nerve circuits in the myenteric and submucosal plexuses. 5-Hydroxytryptamine-induced excitation of the mucosal endings of extrinsic primary afferent neurons contributes to visceral sensation and intestinal motor responses. Because 5-HT is such an important contributor to normal and abnormal function of the gastrointestinal tract, there has been a significant amount of work directed at understanding the molecular and cellular mechanisms by which 5-HT signalling impacts gut function. It is very timely then that Neurogastroenterology and Motility is providing a supplement that covers this important topic area. The supplement is organized to provide readers with an in-depth discussion of the main issues relevant to understanding the physiology and pathophysiology of serotonergic signalling as it relates to motility disturbances in the gut. Dr Mira Wouters and colleagues provide a review and analysis of the literature related to studies of the localization and function of 5-HT receptors to smooth muscle cells, enteric neurons and interstitial cells of Cajals (ICCs) ( 5-HT receptors on interstitial cells of Cajal, smooth muscle and enteric nerves , p. 5). As 5-HT is a neurotransmitter and paracrine signalling molecule, identification of the 5-HT receptor subtypes on neurons and non-neuronal cells is critical for our understanding of normal control of gut motility and for understanding pharmacological treatments of these disorders. Neuronal sites of action for endogenous 5-HT and for serotonergic agents used to treat motility disorders have attracted the most attention from the neurogastroenterology research community. However, 5-HT-related changes in neuronal function can not account for all of the actions of 5-HT on gut motility. Interstitial cells of Cajals regulate smooth muscle rhythmic electrical activity and they also participate in neuromuscular transmission. 5-Hydroxytryptamine modulation of ICC function could alter electrical rhythms in smooth muscle cells and neuromuscular transmission. Indeed, 5-HT4 receptors have been localized to ICCs in the guinea pig and mouse intestine. 5-Hydroxytryptamine or drugs which mimic or block its effects can also alter smooth muscle tone directly. This effect is prominent in the stomach where 5-HT1B/D receptors mediate increases in fundic tone while smooth muscle 5-HT1A receptors mediate relaxation of the fundus. The studies done in mice contrast with those in humans where it was shown that sumatriptan, the 5-HT1B/D receptor agonist, relaxes the Neurogastroenterol Motil (2007) 19 (Suppl. 2), 1–4