Transient receptor potential vanilloid 4 (TRPV4)-dependent calcium influx and ATP release in mouse oesophageal keratinocytes

Hiroshi Mihara, Ammar Boudaka, Toshiro Sugiyama, Yoshinori Moriyama, Makoto Tominaga

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

In the oesophagus the ion channel TRPV4 senses multiple stimuli, including heat and mechanical stimulation. TRPV4 activation causes ATP release from oesophageal cells, which could be important in oesophageal disease mechanisms. Abstract Gastro-oesophageal reflux disease (GERD) is a multi-factorial disease that may involve oesophageal hypersensitivity to mechanical or heat stimulus as well as acids. Intraganglionic laminar endings (IGLEs) are the most prominent terminal structures of oesophageal vagal mechanosensitive afferents and may modulate mechanotransduction via purinergic receptors. Transient receptor potential channel vanilloid 4 (TRPV4) can detect various stimuli such as warm temperature, stretch and some chemicals, including 4α-phorbol 12,13-didecanoate (4α-PDD) and GSK1016790A. TRPV4 is expressed in many tissues, including renal epithelium, skin keratinocytes and urinary bladder epithelium, but its expression and function in the oesophagus is poorly understood. Here, we show anatomical and functional TRPV4 expression in mouse oesophagus and its involvement in ATP release. TRPV4 mRNA and protein were detected in oesophageal keratinocytes. Several known TRPV4 activators (chemicals, heat and stretch stimulus) increased cytosolic Ca 2+ concentrations in cultured WT keratinocytes but not in TRPV4 knockout (KO) cells. Moreover, the TRPV4 agonist GSK1016790A and heat stimulus evoked TRPV4-like current responses in isolated WT keratinocytes, but not in TRPV4KO cells. GSK1016790A and heat stimulus also significantly increased ATP release from WT oesophageal keratinocytes compared to TRPV4KO cells. The vesicle-trafficking inhibitor brefeldin A (BFA) inhibited the ATP release. This ATP release could be mediated by the newly identified vesicle ATP transporter, VNUT, which is expressed by oesophageal keratinocytes at the mRNA and protein levels. In conclusion, in response to heat, chemical and possibly mechanical stimuli, TRPV4 contributes to ATP release in the oesophagus. Thus, TRPV4 could be involved in oesophageal mechano- and heat hypersensitivity.

Original languageEnglish
Pages (from-to)3471-3482
Number of pages12
JournalJournal of Physiology
Volume589
Issue number14
DOIs
Publication statusPublished - Jul 2011

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TRPV Cation Channels
Keratinocytes
Adenosine Triphosphate
Calcium
Hot Temperature
Esophagus
Esophageal Diseases
Hypersensitivity
Epithelium
Transient Receptor Potential Channels
Brefeldin A
Purinergic Receptors
Messenger RNA
Gastroesophageal Reflux
Ion Channels
Urinary Bladder
Proteins

ASJC Scopus subject areas

  • Physiology

Cite this

Transient receptor potential vanilloid 4 (TRPV4)-dependent calcium influx and ATP release in mouse oesophageal keratinocytes. / Mihara, Hiroshi; Boudaka, Ammar; Sugiyama, Toshiro; Moriyama, Yoshinori; Tominaga, Makoto.

In: Journal of Physiology, Vol. 589, No. 14, 07.2011, p. 3471-3482.

Research output: Contribution to journalArticle

Mihara, Hiroshi ; Boudaka, Ammar ; Sugiyama, Toshiro ; Moriyama, Yoshinori ; Tominaga, Makoto. / Transient receptor potential vanilloid 4 (TRPV4)-dependent calcium influx and ATP release in mouse oesophageal keratinocytes. In: Journal of Physiology. 2011 ; Vol. 589, No. 14. pp. 3471-3482.
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