5‐HT secretion by enterochromaffin cells is a very touching story

Gastrointestinal (GI) function is controlled by sympathetic, parasympathetic, sensory and enteric nerves. In addition, the gut mucosa contains enteroendocrine cells which release hormones and paracrine signalling molecules in response to chemical and mechanical stimulation by GI luminal content. Enterochromaffin (EC) cells are an enteroendocrine cell type in the gut mucosa. EC cells release 5-hydroxytryptamine (5-HT) in response to mechanical and chemical stimuli. 5-HT released from EC cells stimulates intestinal motor and secretomotor reflexes by activating 5-HT receptors on terminals of intrinsic primary afferent neurons (IPANS) whose cell bodies are located in the enteric nerve plexuses. IPANS synapse with interneurons which excite other enteric neurons to initiate reflex responses. EC cell-derived 5-HT also acts at 5-HT receptors on extrinsic sensory nerve terminals to convey nociceptive signals to the CNS (via spinal afferents) or to initiate GI reflexes via vagal afferents. TRPA1 channels are chemosensitive ion channels expressed by EC cells and TRPA1 stimulants cause 5-HT release from EC cells (Nowaza et al. 2009). EC cells are also activated by mechanical stimulation and EC cells express unidentified mechanosensitive proteins. The paper by Wang et al. (2017) in this issue of The Journal of Physiology provides exciting new data indicating that Piezo2 is a mechanosensitive ion channel expressed by EC cells. Piezo2 is one of two Piezo ion channels (Piezo1 and Piezo2) expressed by proprioceptive cells (Woo et al. 2015). Piezo2 was also shown to be important for mechanosensation by Aβ nerve fibres that together with Merkel cells (Merkel-cell–neurite complexes) are involved in light touch sensation (Ranade et al. 2014). Piezo channels are large proteins ( 2600 amino acids) and the murine Piezo1 channel has 14 transmembrane spanning domains (Ge et al. 2015). Human Piezo2 has a single channel conductance of 26 pS and the channel inactivates during continuous mechanical stimulation of the cell. Piezo2 is a non-selective cation channel (Irev = 0 mV) with a rank order permeability of Ca2+ > Na+ > K+. The high Ca2+ permeability may be particularly important for EC cell 5-HT release. Wang and co-workers provide immunohistochemical data showing Piezo2 co-localized with 5-HT in EC cells in the human jejunum. Piezo2 was also co-expressed in EC cells in the small intestine of transgenic mice where cyano-fluorescent protein (CFP) expression was driven by the tryptophan hydroxylase-1 (TpH-1) promoter. TpH-1 is the rate limiting enzyme in the 5-HT biosynthetic pathway in EC cells. Piezo2 also co-localized with TpH-1 cells in the mucosa of the mouse jejunum. Wang and colleagues (2017) used QGP-1 cells (an EC cell line) to study mechanically activated inward currents. Mechanical stimulation of QGP-1 cells produced a stimulus intensity-related and rapidly inactivating ( 10 ms) inward current that had a reversal potential near 0 mV. These data suggest that Piezo2 in EC cells is a non-selective cation channel. Mechanically activated currents and 5-HT release from QGP-1 cells were inhibited by Piezo2 siRNA knockdown and by the Piezo2 blockers, Gd3+ and Ruthenium Red and by D-GsMTx4, a mechanosensitive ion channel blocker. The contribution of Piezo2 to intestinal function was assessed using Ussing chambers to measure short circuit currents (ISC) across full thickness preparations of mouse jejunum. Pressure applied to the mucosa evoked an increase in ISC and 5-HT release. These responses were inhibited by mucosally applied Gd3+, Ruthenium Red and GsMTX4, suggesting that Piezo2 blockers act directly on EC cells. Previous ultrastructural studies in the mouse duodenum revealed close appositions between the basolateral surface of EC cells and nerve fibres (Wade & Westfall, 1985) These subepithelial nerve fibres could be targets for 5-HT released from EC cells. Wang et al. (2017) found that the 5-HT3 and 5-HT4 receptor antagonists ondansetron and GR 113808 blocked pressure-evoked ISC when the drugs were applied to the basolateral (serosal) but not mucosal surface of the tissue. It is possible that 5-HT diffuses (at least in ex vivo preparations) to the nerve plexuses to activate secretomotor circuits. However, these data do not yet rule out the possibility of direct subepithelial nerve fibre activation by EC cell 5-HT. 5-HT released from EC cells participates in several physiological (gut secretion, for example) and pathophysiological (GI pain) responses in the gut. The irritable bowel syndrome (IBS) is a gastrointestinal motility/sensation disorder in which EC cell 5-HT release is a key player. Intestinal Piezo2 might be a target for new drugs that could treat IBS or other disorders associated with excessive 5-HT release from EC cells.