Protease-activated receptor 2-Transient receptor potential vanilloid 4 signaling complex (PAR2-TRPV4)

The Protease-activated receptor 2-Transient receptor potential vanilloid 4 (PAR2-TRPV4) coupling is a specialized signaling mechanism where the activation of the G protein-coupled receptor PAR2 sensitizes the TRPV4 ion channel. This interaction typically occurs on the plasma membrane of nociceptive neurons and epithelial cells, facilitating the transduction of inflammatory stimuli into electrical signals. Proteases such as tryptase or trypsin cleave the N-terminus of PAR2, triggering a signaling cascade involving phospholipase C (PLC) and protein kinases (PKA/PKC) that phosphorylate and activate TRPV4 (Poole et al., 2013, J Biol Chem). This synergy results in enhanced calcium influx and the release of pro-inflammatory neuropeptides like Substance P and Calcitonin Gene-Related Peptide (CGRP). The PAR2-TRPV4 axis is a significant therapeutic target for treating chronic inflammatory conditions, visceral hypersensitivity in irritable bowel syndrome, and various forms of pruritus (Cenac et al., 2007, J Clin Invest). Pharmacological intervention usually involves small molecule antagonists of either PAR2 or TRPV4 to disrupt this pro-nociceptive signaling pathway.

Other names

PAR2-TRPV4 axisPAR2-TRPV4 signaling pathwayF2RL1-TRPV4 interactionPAR2-TRPV4 functional coupling

PAR2 activation by proteases triggers intracellular signaling (PLC/PKC/PKA) that sensitizes TRPV4, leading to increased calcium influx and neuronal excitation.