Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases

Abstract

Inflammatory diseases have become increasingly prevalent with industrialization. To address this, numerous anti-inflammatory agents and molecular targets have been considered in clinical trials. Among molecular targets, protease-activated receptors (PARs) are abundantly recognized for their roles in the development of chronic inflammatory diseases. In particular, several inflammatory effects are directly mediated by the sensing of proteolytic activity by PARs. PARs belong to the seven transmembrane domain G protein-coupled receptor family, but are unique in their lack of physiologically soluble ligands. In contrast with classical receptors, PARs are activated by N-terminal proteolytic cleavage. Upon removal of specific N-terminal peptides, the resulting N-termini serve as tethered activation ligands that interact with the extracellular loop 2 domain and initiate receptor signaling. In the classical pathway, activated receptors mediate signaling by recruiting G proteins. However, activation of PARs alternatively lead to the transactivation of and signaling through receptors such as co-localized PARs, ion channels, and toll-like receptors. In this review we consider PARs and their modulators as potential therapeutic agents, and summarize the current understanding of PAR functions from clinical and in vitro studies of PAR-related inflammation.

BRET sensors unravel thatPlasmodium falciparumserpentine receptor 12 (PfSR12) increases surface expression of mammalian GPCRs in HEK293 cells

“…Taken together, these result indicate that the increase of the observed Gq signaling is not due to the direct action thrombin or carbamoyl choline on PfSR12, but rather to an increase of plasma membrane PAR and M3 receptors endogenously expressed in HEK293 cells and capable of triggering signaling. In fact, PAR and M3R have the same signaling profile observed in this work: PAR1 and PAR4, the main thrombin receptors that are endogenously expressed in HEK293 cells (Atwood et al 2011), couple with the Gq/11 family but not with Gs (Heuberger and Schuepbach 2019).…”

Targeting Proteases in Cystic Fibrosis Lung Disease. Paradigms, Progress, and Potential

“…Matrix degradation Serine, cysteine, MMP (52,54,55,70) Cytokine processing Serine, cysteine, MMP (14,18,46,56) Cytokine upregulation Serine, cysteine, MMP (15,48,54,55) PAR activation Serine, cysteine, MMP (48,71) Trans-class protease activation Serine, cysteine (9,12,26,27) Host defence protein degradation (including antiproteases)…”

Epigenetic regulator miRNA pattern differences among SARS-CoV, SARS-CoV-2 and SARS-CoV-2 world-wide isolates delineated the mystery behind the epic pathogenicity and distinct clinical characteristics of pandemic COVID-19

“…which can be hijacked by viruses for their efficient replication, pre-mRNA processing and translation (Figure 5A). These host miRNAs might also try to reduce some host induced inflammatory responses to prevent acute lung damage by targeting IGF1 signaling (Li et al, 2019), VEGF signaling (Alkharsah, 2018), PAR1 signaling (Heuberger and Schuepbach, 2019), integrin signaling (Teoh et al, 2015), TGF-beta signaling (Denney et al, 2018), TRAIL signaling (Cummins and Badley, 2009), etc (Figure 5A). Some signaling pathways like-CXCR4 signaling (Arnolds and Spencer, 2014), TGF-beta signaling (Denney et al, 2018), mTOR signaling (Le Sage et al, 2016), PI3K-Akt signaling (Diehl and Schaal, 2013), etc.…”