title: The TRPV4 channel is a novel regulator of intracellular Ca2+ in human esophageal epithelial cells.
abstract: The esophageal epithelium has sensory properties that enable it to sustain normal barrier function. Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+)-permeable channel that is activated by extracellular hypotonicity, polyunsaturated fatty acids, phorbol esters, and elevated temperature. We found that TRPV4 is expressed in both human esophageal tissue and in HET-1A cells, a human esophageal epithelial cell line. Specific activation of TRPV4 by the phorbol ester 4α-phorbol 12,13-didecanoate (4α-PDD) increased intracellular Ca(2+) in a subset of HET-1A cells. Elevated temperature strongly potentiated this effect at low concentrations of 4α-PDD, and all of the responses were inhibited by the TRPV antagonist ruthenium red. TRPV4 activation differentially affected cell proliferation and cell viability; HET-1A cell proliferation was increased by 1 μM 4α-PDD, whereas higher concentrations (10 μM and 30 μM) significantly decreased cell viability. Transient TRPV4 activation triggered ATP release in a concentration-dependent manner via gap-junction hemichannels, including pannexin 1 and connexin 43. Furthermore, TRPV4 activation for 24 h did not increase the production of interleukin 8 (IL-8) but reduced IL-1β-induced IL-8 production. Small-interference RNA targeted to TRPV4 significantly attenuated all of the 4α-PDD-induced responses in HET-1A cells. Collectively, these findings suggest that TRPV4 is a novel regulator of Ca(2+)-dependent signaling pathways linked to cell proliferation, cell survival, ATP release, and IL-8 production in human esophageal epithelial cells.
authors.affiliation: Department of Neurobiology and Anatomy, Graduate School of Medical Sciences, Nagoya City University, Japan. tueda@med.nagoya-cu.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueda
authors.forename: Michiko
authors.initials: M
authors.lastname: Shikano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kamiya
authors.forename: Takashi
authors.initials: T
authors.lastname: Joh
authors.forename: Shinya
authors.initials: S
authors.lastname: Ugawa
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D004947:Esophagus / Q000378:metabolism*; D017629:Gap Junctions / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010704:Phorbols / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D012430:Ruthenium Red / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C517592:4alpha-phorbol 12,13-didecanone; D018031:Connexin 43; D017630:Connexins; C500216:GJA1 protein, human; D053583:Interleukin-1beta; D016209:Interleukin-8; D009419:Nerve Tissue Proteins; C492764:PANX1 protein, human; D010704:Phorbols; D034741:RNA, Small Interfering; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D012430:Ruthenium Red; D000255:Adenosine Triphosphate; D002118:Calcium