Serotonin as a Mitogen in the Gastrointestinal Tract: Revisiting a Familiar Molecule in a New Role

Abstract

Serotonin signaling is ubiquitous in the gastrointestinal (GI) system, where it acts as a neurotransmitter in the enteric nervous system (ENS) and influences intestinal motility and inflammation. Since its discovery, serotonin has been linked to cellular proliferation in several types of tissues, including vascular smooth muscle, neurons, and hepatocytes. Activation of serotonin receptors on distinct cell types has been shown to induce well-known intracellular proliferation pathways. In the GI tract, potentiation of serotonin signaling results in enhanced intestinal epithelial proliferation, and decreased injury from intestinal inflammation. Furthermore, activation of the type 4 serotonin receptor on enteric neurons leads to neurogenesis and neuroprotection in the setting of intestinal injury. It is not surprising that the mitogenic properties of serotonin are pronounced within the GI tract, where enterochromaffin cells in the intestinal epithelium produce 90% of the body's serotonin; however, these proliferative effects are attributed to increased serotonin signaling within the ENS compartment as opposed to the intestinal mucosa, which are functionally and chemically separate by virtue of the distinct tryptophan hydroxylase enzyme isoforms involved in serotonin synthesis. The exact mechanism by which serotonergic neurons in the ENS lead to intestinal proliferation are not known, but the activation of muscarinic receptors on intestinal crypt cells indicate that cholinergic signaling is essential to this signaling pathway. Further understanding of serotonin's role in mucosal and enteric nervous system mitogenesis may aid in harnessing serotonin signaling for therapeutic benefit in many GI diseases, including inflammatory bowel disease, malabsorptive conditions, and cancer.

Keywords: Enteric Nervous System; Intestinal Epithelium; Mitogenesis.

Figure 1

Life cycle of serotonin in the intestinal epithelium and ENS. 5-HT is synthesized from tryptophan in enterochromaffin cells and in enteric neurons by distinct isoforms of TPH, respectively. TPH1-derived 5-HT in the mucosa enters the portal circulation, where it is stored in platelets that enter the systemic circulation. Serotonergic neurons in the ENS produce TPH2 to synthesize 5-HT, which is stored in synaptic vesicles. Upon release from intracellular vesicles or platelets, 5-HT binds to 5-HTRs on cell membranes. The majority of 5-HTRs are G-protein–coupled receptors, with the exception of the 5-HT₃–receptor family, which are ligand-gated ion channels. The SERT is important in inactivating 5-HT by relocating the molecule intracellularly, where it subsequently is degraded by monoamine oxidase into 5-hydroxyindoleacetic acid (5-HIAA). IPAN, intrinsic primary afferent neuron; MAO, monoamine oxidase; Trp, tryptophan.

Figure 2

Diagram of physiologic and pathologic processes in which serotonin exerts mitogenic effects. Potentiation of serotonin signaling leads to activation of cellular proliferation signaling pathways in diverse cell types. 5-HT receptors, namely 5-HTR_1B and 5-HTR_2A, and SERT play a role in smooth muscle proliferation seen in idiopathic pulmonary hypertension. 5-HTR_2A and 5-HTR_2C on hepatocytes are involved in liver regeneration after partial hepatectomy. 5-HT–receptor binding leads to uncontrolled cellular division and metastatic potential in multiple cancers. Intact 5-HT signaling is necessary for normal embryonic development, and 5-HT–receptor binding is central to neurogenesis.

Figure 3

Schematic of serotonergic and cholinergic receptors in the intestinal epithelium. The intestinal crypt is composed of intestinal stem cells and undifferentiated transit-amplifying cells, whose division underlies epithelial proliferation. Neuronal serotonin, synthesized by TPH2 in the enteric nervous system, leads to epithelial proliferation both through direct binding of 5-HTR on epithelial cells, and indirectly via a cholinergic pathway that leads to muscarinic-receptor activation of intestinal crypt cells.