Fig. 2.

Proposed molecular mechanism of visceral hypersensitivity or blunting with TRPV4 enhancement or suppression. a Formation of major metabolites generated from the AA cascade. CYP enzymes convert arachidonic acid into EETs. Increased amounts of 5,6-EET or 8,9-EET then activate TRPV4. b TRPV4 expressed in gastrointestinal epithelia is activated by stretch, heat, hypo-osmolality, LPS or the endogenous activators (5,6-EET and 8,9-EET). Several factors (e.g., proteases such as trypsin and tryptase, TNFα, serotonin, histamine, IL-17) enhance TRPV4 function. TRPV4 activation induces VNUT-mediated ATP exocytosis and increases cellular permeability. Acid also induces ATP release via another mechanism to induce visceral hypersensitivity. c Methylation-silencing of TRPV4 expression decreases epithelial sensitivity to physiological stimuli resulting in diminished visceral responses. AA, arachidonic acid; CYP, Cytochrome P450; EET, epoxyeicosatrienoic acids; TRPV4, transient receptor potential vanilloid 4; LPS, lipopolysaccharides; VNUT, vesicular nucleotide transporter; ATP, adenosine triphosphate; TNFα, tumor necrosis factor-α; IL-17, interleukin-17; PG, prostaglandin; LT, leukotriene; COX, cyclooxygenase; LOX, lipoxygenase.