PAR-2 activation enhances weak acid-induced ATP release through TRPV1 and ASIC sensitization in human esophageal epithelial cells

Abstract

Esophageal visceral hypersensitivity has been proposed to be the pathogenesis of heartburn sensation in nonerosive reflux disease. Protease-activated receptor-2 (PAR-2) is expressed in human esophageal epithelial cells and is believed to play a role in inflammation and sensation. PAR-2 activation may modulate these responses through adenosine triphosphate (ATP) release, which is involved in transduction of sensation and pain. The transient receptor potential vanilloid receptor 1 (TRPV1) and acid-sensing ion channels (ASICs) are both acid-sensitive nociceptors. However, the interaction among these molecules and the mechanisms of heartburn sensation are still not clear. We therefore examined whether ATP release in human esophageal epithelial cells in response to acid is modulated by TRPV1 and ASICs and whether PAR-2 activation influences the sensitivity of TRPV1 and ASICs. Weak acid (pH 5) stimulated the release of ATP from primary human esophageal epithelial cells (HEECs). This effect was significantly reduced after pretreatment with 5-iodoresiniferatoxin (IRTX), a TRPV1-specific antagonist, or with amiloride, a nonselective ASIC blocker. TRPV1 and ASIC3 small interfering RNA (siRNA) transfection also decreased weak acid-induced ATP release. Pretreatment of HEECs with trypsin, tryptase, or a PAR-2 agonist enhanced weak acid-induced ATP release. Trypsin treatment led to the phosphorylation of TRPV1. Acid-induced ATP release enhancement by trypsin was partially blocked by IRTX, amiloride, or a PAR-2 antagonist. Conversely, acid-induced ATP release was augmented by PAR-2 activation through TRPV1 and ASICs. These findings suggested that the pathophysiology of heartburn sensation or esophageal hypersensitivity may be associated with the activation of PAR-2, TRPV1, and ASICs.

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“…GABA and glycine are mainly inhibitory mediators in the SC [30,31]. A recent study also demonstrated that the expression of TRPV1 in peripheral nerve fibers was significantly increased after EA stimulation of acupoints but not non-acupoint meridians or non-meridian control skin [1].…”

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“…It is involved in the mediation of various pain qualities during in ammation, ischemia or cancer metastases, which involve a decrease in the pH of the cellular interstitium of cutaneous or muscle tissue [28][29]. Research studies have shown that ASIC3 is highly involved in the decrease of the pain threshold in an in ammatory environment and in the development of esophageal hypersensitivity [30]. Our study showed that the mRNA and protein expressions of ASIC3 in DRG were signi cantly elevated in rats of the HSP group, compared with that of rats in the NC group.…”

Reflux hypersensitivity - what is in the name?

“…The latter may be associated with an activation of TRPV-1 and protease-activated receptor 2 (PAR2) 20 . Furthermore, one study demonstrated that the activation of PAR2 mediates the sensitization of TRPV-1 and acid-sensing ion channels (ASICs) and enhances weak acid-induced ATP release from esophageal epithelial cells 21 . These findings suggested that the pathogenesis of heartburn sensation in patients with reflux hypersensitivity or the esophageal hypersensitivity to physiologic amounts of acid exposure is the activation of PAR2, TRPV-1, and ASICs.…”