Protease-activated receptors (PARs) and the neurokinin 1 receptor (NK1R) belong to the G protein-coupled receptor (GPCR) family. In this review, we focus on the regulatory mechanism of ectodomain shedding by ADAM10/17 metalloprotease via GPCR signaling. PAR2 and NK1R induce membrane blebbing, resulting in phosphatidylserine externalization in the cellular membrane, which is required for ADAM10/17 metalloprotease activation. Membrane-embedded dual oxidase 2 (DUOX2) has NADPH oxidase and peroxidase domains. NADPH oxidase domain generates hydrogen peroxide (H₂O₂), while the peroxidase domain produces peroxynitrite (ONOO⁻) through the interaction of nitrogen oxide with superoxide. Both H₂O₂ and peroxynitrite activate ADAM10/17 metalloproteases. PAR2 signaling activates ADAM10/17 by NADPH-mediated H₂O₂, leading to the transactivation of DUOX2/EGFR/TLR4 to synergistically upregulate IL-12p40 production after exposure to LPS. In contrast, nitric oxide (NO) synthesis is promoted by NK1R signaling, and DUOX2 generates ONOO-, preferentially activating ADAM10/17 metalloprotease. Ectodomain shedding of membrane-bound fractalkine is mediated by ADAM10/17. Substance P (SP)/NK1R signals enhance shedding of membrane-bound fractalkine, whereas small interfering RNA for DUOX2 further increases membrane-bound fractalkine but decreases soluble fractalkine compared with cells treated with SP alone. Considering the signaling pathway of TGFβ1 (an inhibitor of iNOS mRNA expression), silencing of RNA for TAK-1 upregulates membrane-bound fractalkine tripartite motif 28 (TRIM28)/transcriptional intermediary factor 1β (TIF1β) functions as an E3 ubiquitin ligase and specificity protein 1 negatively regulate TGFβ1 levels to upregulate the generation of peroxynitrite, leading to increased shedding of membrane-bound fractalkine via SP/NK1R signaling. DUOX2 plays a pivotal role for ectodomain shedding through ADAM10/17 activation by GPCR signaling.

GPCR, DUOX2, ADAM family, Peroxynitrite, Shedding