The serotonin-secreting neuron not only secretes serotonin, but it also takes up the secreted serotonin that is in the space between the two neurons. This is the space between a serotonin-secreting neuron and a serotonin-responding neuron that contains the serotonin receptors. One model that has proved useful in understanding serotonin action is the synaptic cleft. The serotonin subtypes mediate a variety of physiological responses in the GI tract, responses include activation of secretory cells, afferent and efferent neuron activation, and direct effects on gut smooth muscle resulting in either smooth muscle contraction or smooth muscle relaxation. Various medications are agonists (stimulators) of specific serotonin subtypes, and other medications are antagonists (blockers) of specific serotonin subtypes. The 5-HT4 subtype is positively coupled to adenylyl cyclase. However, the exact mechanism of stimulation is not known for all of the serotonin receptor subtypes. These serotonin receptors are coupled to a so-called G protein that delivers serotonin-stimulated intracellular messages. Within each class, subtypes are further designated by an additional letter (e.g., 5-HT1A or 5-HT1B). There are seven different serotonin receptor classes designated 5-HT1 through 5-HT7.
Feldman, in Encyclopedia of Gastroenterology, 2004 Physiological EffectsĬirculating serotonin attaches to serotonin receptors that are located on the cell membrane. 163 It has been proposed that melatonin released after a meal may contribute to postprandial somnolence. A number of actions on the GI tract have been described for melatonin, including reducing gastric acid and pepsin secretion, inducing smooth muscle relaxation, and preventing epithelial injury through an antioxidant effect. Melatonin is produced in enterochromaffin cells and released into the blood after ingestion of a meal. 162 Other than the pineal gland, the GI tract is the major source of the body’s melatonin. Serotonin can also be enzymatically converted to melatonin by serotonin N-acetyltransferase. 5-HT4 receptor agonists elicit prokinetic effects and are used to treat constipation-predominant irritable bowel syndrome and other motility disorders. For example, 5-HT3 receptor antagonists, which reduce intestinal secretion, are used to treat diarrhea-predominant irritable bowel syndrome. 159 Characterization of specific serotonin receptor subtypes has led to the development of selective agonists and antagonists for the treatment of irritable bowel syndrome and chronic constipation and diarrhea. Serotonin and its receptor have been implicated in the pathogenesis of motility disorders of the GI tract. Because of these diverse effects, it is not surprising that selective serotonin reuptake inhibitor drugs (SSRIs), commonly used to treat depression and anxiety, have prominent GI side effects when compared with placebo treatment. Serotonin may also activate vagal afferent pathways and, in the central nervous system, modulates appetite, mood, and sexual function. Intrinsic neurons activated by serotonin are primary components of the peristaltic and secretory reflexes responsible for normal GI function. Extrinsic neurons activated by serotonin participate in bowel sensation and may be responsible for abdominal pain, nausea, and symptoms associated with irritable bowel syndrome. 156 The myenteric plexus contains serotoninergic interneurons that project to the submucosal plexus and ganglia extrinsic to the bowel wall. 157 Serotonin released from mucosal cells stimulates sensory neurons, initiating a peristaltic reflex and secretion (via 5-HT4 receptors), and modulates sensation through activation of 5-HT3 receptors. 158 It can cause smooth muscle contraction through stimulation of cholinergic nerves or relaxation by stimulating inhibitory NO-containing neurons. The actions of serotonin are complex ( Fig. There are seven different serotonin receptor subtypes found on enteric neurons, enterochromaffin cells, and GI smooth muscle (5-HT1 to 5-HT7). Serotonin mediates its effects by binding to a specific receptor.
Most plasma serotonin is derived from the gut, where it is found in mucosal enterochromaffin cells and the enteric nervous system.
Secreted serotonin is inactivated in the synaptic cleft by reuptake via a serotonin-specific transporter. 157 Serotonin is synthesized from tryptophan, an essential amino acid, and is converted to its active form in nerve terminals. 156 The GI tract contains more than 95% of the total body serotonin, and serotonin is important in various processes, including epithelial secretion, bowel motility, nausea, and emesis. Serotonin has long been known to play a role in GI neurotransmission. Mark Feldman MD, in Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 2021 Serotonin
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