The Serotonin Signaling System: From Basic Understanding To Drug Development for Functional GI Disorders  Michael D. Gershon, Jan Tack  Gastroenterology  Volume 132, Issue 1, Pages 397-414 (January 2007) DOI: 10.1053/j.gastro.2006.11.002 Copyright © 2007 AGA Institute Terms and Conditions

Figure 1 An electron micrograph of an EC cell from the mouse ileum. Note the clustering of dark serotonin-containing storage granules in the basolateral cytoplasm. Serotonin is released (5-HT, arrow) into the loose areolar connective tissue of the lamina propria where it can gain access to nerve fibers (nerve). After it has acted on 5-HT3 (extrinsic nerves; myenteric IPANs) or 5-HT1P (submucosal IPANs) receptors expressed by these nerves, serotonin is inactivated by SERT-mediated uptake (dotted arrow) into enterocytes where it is catabolized. The marker = 500 nm. Gastroenterology 2007 132, 397-414DOI: (10.1053/j.gastro.2006.11.002) Copyright © 2007 AGA Institute Terms and Conditions

Figure 2 Illustration showing actions of serotonin in the bowel wall. EC cells in the mucosal epithelium secrete serotonin (5-HT) in response to pressure or other appropriate stimuli (arrows). Serotonin can stimulate extrinsic (not illustrated) or intrinsic primary afferent neurons (IPANs). IPANs are located in submucosal and myenteric plexuses. Submucosal IPANs are activated by 5-HT1P receptors, while myenteric IPANs are activated by 5-HT3 receptors. Both submucosal and myenteric IPANs are cholinergic, but submucosal IPANs also release CGRP. Release of ACh and CGRP from IPANs is amplified by 5-HT4 receptors, which are presynaptic. Myenteric IPANs (Dogiel type II neurons) are thought to project multiples processes and terminate on numerous other cells. Following the action of serotonin, it is inactivated by SERT-mediated uptake into enterocytes. Submucosal IPANs have been linked to mucosally driven peristaltic and secretory reflexes, while myenteric IPANs have been associated with giant migrating contractions. Gastroenterology 2007 132, 397-414DOI: (10.1053/j.gastro.2006.11.002) Copyright © 2007 AGA Institute Terms and Conditions

Figure 3 An electron micrograph showing a portion of the myenteric plexus (MyP), a nearby smooth muscle cell and an interstitial cell of Cajal (ICC). A cholinergic synapse is illustrated. Note the cluster of small (50 nm diameter) clear synaptic vesicles around a presynaptic density (active zone). The postsynaptic element is an extremely attenuated neurite. The myenteric plexus contains millions of synapses, most of which are on fine processes, such as the one illustrated here, suggesting that neuronal activity is capable of a degree of modulation that is difficult to study by current techniques, which record mainly activity in nerve cell bodies. Most synapses, like this one, are cholingergic. Gastroenterology 2007 132, 397-414DOI: (10.1053/j.gastro.2006.11.002) Copyright © 2007 AGA Institute Terms and Conditions

Figure 4 Typical profiles of 5-hydroxytryptamine (5-HT) concentrations before and after a standardized meal in individual patients with constipation (■)- and diarrhea (●)-predominant IBS and healthy controls (▲). From reference Atkinson et al.125 Gastroenterology 2007 132, 397-414DOI: (10.1053/j.gastro.2006.11.002) Copyright © 2007 AGA Institute Terms and Conditions