title: Mechanosensitive ion channel Piezo2 is important for enterochromaffin cell response to mechanical forces.
abstract: The gastrointestinal epithelial enterochromaffin (EC) cell synthesizes the vast majority of the body's serotonin. As a specialized mechanosensor, the EC cell releases this serotonin in response to mechanical forces. However, the molecular mechanism of EC cell mechanotransduction is unknown. In the present study, we show, for the first time, that the mechanosensitive ion channel Piezo2 is specifically expressed by the human and mouse EC cells. Activation of Piezo2 by mechanical forces results in a characteristic ionic current, the release of serotonin and stimulation of gastrointestinal secretion. Piezo2 inhibition by drugs or molecular knockdown decreases mechanosensitive currents, serotonin release and downstream physiological effects. The results of the present study suggest that the mechanosensitive ion channel Piezo2 is specifically expressed by the EC cells of the human and mouse small bowel and that it is important for EC cell mechanotransduction.
  
  
  
  The enterochromaffin (EC) cell in the gastrointestinal (GI) epithelium is the source of nearly all systemic serotonin (5-hydroxytryptamine; 5-HT), which is an important neurotransmitter and endocrine, autocrine and paracrine hormone. The EC cell is a specialized mechanosensor, and it is well known that it releases 5-HT in response to mechanical forces. However, the EC cell mechanotransduction mechanism is unknown. The present study aimed to determine whether Piezo2 is involved in EC cell mechanosensation. Piezo2 mRNA was expressed in human jejunum and mouse mucosa from all segments of the small bowel. Piezo2 immunoreactivity localized specifically within EC cells of human and mouse small bowel epithelium. The EC cell model released 5-HT in response to stretch, and had Piezo2 mRNA and protein, as well as a mechanically-sensitive inward non-selective cation current characteristic of Piezo2. Both inward currents and 5-HT release were inhibited by Piezo2 small interfering RNA and antagonists (Gd3+and D-GsMTx4). Jejunum mucosal pressure increased 5-HT release and short-circuit current via submucosal 5-HT3 and 5-HT4 receptors. Pressure-induced secretion was inhibited by the mechanosensitive ion channel antagonists gadolinium, ruthenium red and D-GsMTx4. We conclude that the EC cells in the human and mouse small bowel GI epithelium selectively express the mechanosensitive ion channel Piezo2, and also that activation of Piezo2 by force leads to inward currents, 5-HT release and an increase in mucosal secretion. Therefore, Piezo2 is critical to EC cell mechanosensitivity and downstream physiological effects.
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology & Hepatology, Departments of Medicine and Physiology & Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.|Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 300 Yanchang Middle Road, Shanghai, PR China.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology & Hepatology, Departments of Medicine and Physiology & Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Knutson
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology & Hepatology, Departments of Medicine and Physiology & Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
authors.forename: Constanza
authors.initials: C
authors.lastname: Alcaino
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology & Hepatology, Departments of Medicine and Physiology & Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Linden
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology & Hepatology, Departments of Medicine and Physiology & Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Gibbons
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology & Hepatology, Departments of Medicine and Physiology & Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
authors.forename: Purna
authors.initials: P
authors.lastname: Kashyap
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology & Hepatology, Departments of Medicine and Physiology & Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
authors.forename: Madhusudan
authors.initials: M
authors.lastname: Grover
authors.affiliation: Division of Pulmonary and Critical Care, Departments of Medicine and Physiology & Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Oeckler
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gottlieb
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Massachusetts Medical School, 55 N Lake Ave, Worcester, MA, USA.
authors.forename: Hui Joyce
authors.initials: HJ
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Massachusetts Medical School, 55 N Lake Ave, Worcester, MA, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Leiter
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology & Hepatology, Departments of Medicine and Physiology & Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology & Hepatology, Departments of Medicine and Physiology & Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Beyder
mesh_terms: D000818:Animals; D002460:Cell Line; D004759:Enterochromaffin Cells / Q000502:physiology*; D006801:Humans; D007413:Intestinal Mucosa / Q000502:physiology; D007421:Intestine, Small / Q000502:physiology; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D010812:Physical Stimulation; D011312:Pressure; D012333:RNA, Messenger / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
chemical_list: D007473:Ion Channels; C000589132:PIEZO2 protein, human; C552921:Piezo2 protein, mouse; D012333:RNA, Messenger; D012701:Serotonin
keywords: enterochromaffin cell; mechanosensitive ion channel; mechanotransduction; serotonin