TY - JOUR
T1 - Mechanosensory signaling in enterochromaffin cells and 5-HT release
T2 - Potential implications for gut inflammation
AU - Linan-Rico, Andromeda
AU - Ochoa-Cortes, Fernando
AU - Beyder, Arthur
AU - Soghomonyan, Suren
AU - Zuleta-Alarcon, Alix
AU - Coppola, Vincenzo
AU - Christofi, Fievos L.
N1 - Funding Information:
FC received support from NIH R01 (DK093499), NCRR (S10RR11434), strategic initiative funds from Anesthesiology and The Ohio State University. AB received support from NIH K08 (DK106456), a Pilot and Feasibility Grant from Mayo Clinic Center for Cell Signaling in Gastroenterology (NIH P30DK084567) and a 2015 American Gastroenterological Association Research Scholar Award (AGA RSA).
Publisher Copyright:
© 2016 Linan-Rico, Ochoa-Cortes, Beyder, Soghomonyan, Zuleta-Alarcon, Coppola and Christofi.
PY - 2016
Y1 - 2016
N2 - Enterochromaffin (EC) cells synthesize 95% of the body 5-HT and release 5-HT in response to mechanical or chemical stimulation. EC cell 5-HT has physiological effects on gut motility, secretion and visceral sensation. Abnormal regulation of 5-HT occurs in gastrointestinal disorders and Inflammatory Bowel Diseases (IBD) where 5-HT may represent a key player in the pathogenesis of intestinal inflammation. The focus of this review is on mechanism(s) involved in EC cell "mechanosensation" and critical gaps in our knowledge for future research. Much of our knowledge and concepts are from a human BON cell model of EC, although more recent work has included other cell lines, native EC cells from mouse and human and intact mucosa. EC cells are "mechanosensors" that respond to physical forces generated during peristaltic activity by translating the mechanical stimulus (MS) into an intracellular biochemical response leading to 5-HT and ATP release. The emerging picture of mechanosensation includes Piezo 2 channels, caveolin-rich microdomains, and tight regulation of 5-HT release by purines. The "purinergic hypothesis" is that MS releases purines to act in an autocrine/paracrine manner to activate excitatory (P2Y1, P2Y4, P2Y6, and A2A/A2B) or inhibitory (P2Y12, A1, and A3) receptors to regulate 5-HT release. MS activates a P2Y1/Gαq/PLC/IP3-IP3R/SERCA Ca2+ signaling pathway, an A2A/A2B-Gs/AC/cAMP-PKA signaling pathway, an ATP-gated P2X3 channel, and an inhibitory P2Y12-Gi/o/AC-cAMP pathway. In human IBD, P2X3 is down regulated and A2B is up regulated in EC cells, but the pathophysiological consequences of abnormal mechanosensory or purinergic 5-HT signaling remain unknown. EC cell mechanosensation remains poorly understood.
AB - Enterochromaffin (EC) cells synthesize 95% of the body 5-HT and release 5-HT in response to mechanical or chemical stimulation. EC cell 5-HT has physiological effects on gut motility, secretion and visceral sensation. Abnormal regulation of 5-HT occurs in gastrointestinal disorders and Inflammatory Bowel Diseases (IBD) where 5-HT may represent a key player in the pathogenesis of intestinal inflammation. The focus of this review is on mechanism(s) involved in EC cell "mechanosensation" and critical gaps in our knowledge for future research. Much of our knowledge and concepts are from a human BON cell model of EC, although more recent work has included other cell lines, native EC cells from mouse and human and intact mucosa. EC cells are "mechanosensors" that respond to physical forces generated during peristaltic activity by translating the mechanical stimulus (MS) into an intracellular biochemical response leading to 5-HT and ATP release. The emerging picture of mechanosensation includes Piezo 2 channels, caveolin-rich microdomains, and tight regulation of 5-HT release by purines. The "purinergic hypothesis" is that MS releases purines to act in an autocrine/paracrine manner to activate excitatory (P2Y1, P2Y4, P2Y6, and A2A/A2B) or inhibitory (P2Y12, A1, and A3) receptors to regulate 5-HT release. MS activates a P2Y1/Gαq/PLC/IP3-IP3R/SERCA Ca2+ signaling pathway, an A2A/A2B-Gs/AC/cAMP-PKA signaling pathway, an ATP-gated P2X3 channel, and an inhibitory P2Y12-Gi/o/AC-cAMP pathway. In human IBD, P2X3 is down regulated and A2B is up regulated in EC cells, but the pathophysiological consequences of abnormal mechanosensory or purinergic 5-HT signaling remain unknown. EC cell mechanosensation remains poorly understood.
KW - ENS
KW - Enterochromaffin
KW - Inflammation
KW - Mechanotransduction
KW - Piezo 2
KW - Purinergic receptors
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U2 - 10.3389/fnins.2016.00564
DO - 10.3389/fnins.2016.00564
M3 - Review article
AN - SCOPUS:85009799187
SN - 1662-4548
VL - 10
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
IS - DEC
M1 - 564
ER -