Protease-activated receptors in health and disease

Abstract

Although generally regarded as degradatory enzymes, certain proteases are also signaling molecules that specifically control cellular functions by cleaving protease-activated receptors (PARs). The four known PARs are members of the large family of G protein-coupled receptors. These transmembrane receptors control most physiological and pathological processes and are the target of a large proportion of therapeutic drugs. Signaling proteases include enzymes from the circulation, from immune, inflammatory epithelial and cancer cells, as well as from commensal and pathogenic bacteria. Advances in our understanding of the structure and function of PARs provide insights into how diverse proteases activate these receptors to regulate physiological and pathological processes in most tissues and organ systems. The realization that proteases and PARs are key mediators of disease, coupled with advances in understanding the atomic level structure of PARs and their mechanisms of signaling in subcellular microdomains, has spurred the development of antagonists, some of which have advanced to the clinic. Herein we review the discovery, structure and function of this receptor system, highlight the contribution of PARs to homeostatic control, and discuss the potential of PAR antagonists for the treatment of major diseases.

DNA-Methylation Signatures of Tobacco Smoking in a High Cardiovascular Risk Population: Modulation by the Mediterranean Diet

“…Even though the CpGs only found in the EPIC 850 K array are more recent, they have also been reported in previous studies that have used this array [ 51 , 55 , 61 , 107 ]. This result confirms the high consistency of the effect of tobacco smoking on DNA methylation in diverse populations and the relevance of genes related to inflammation and immunity pathways (AHRR, F2RL3 and PRSS23, among others) [ 108 , 109 ]. However, it is worth noting that, despite the consistency in detecting various CpGs as statistically significant, the contribution of each of them may differ and be more specific to each population.…”

Single-cell analysis reveals melanocytes may promote inflammation in chronic wounds through cathepsin G

“…PARs are G-protein-coupled receptors, activated by cleavage of their N-terminal domains by serine proteases, which are seven-transmembrane domain receptors also comprising PAR1, 2(F2RL1), 3, and 4 ( Coelho et al, 2003 ). PARs are involved in the regulation of cardiac, skin, arthritis, and respiratory system physiological and pathophysiological functions and are the target of therapeutic drugs ( Schmidlin et al, 2002 ; Gieseler et al, 2013 ; Oikonomopoulou et al, 2018 ; Carroll et al, 2021 ; Peach et al, 2023 ).…”

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…As a result, allosteric regulators of the PARs with antagonistic or NAM activity can be used to prevent thrombosis, attenuate endothelial dysfunctions in sepsis, and also as anticancer drugs. In turn, allosteric agonists and PAMs may be useful for increasing cell survival and wound healing [243,255,256].…”

“…significant progress has now been made in the development of allosteric regulators of the PAR family of GPCRs. This family includes 4 types of PARs (PAR1, PAR2, PAR3, and PAR4), which are critical for the control of hemostasis and platelet function, are involved in the regulation of embryonic development, inflammation, wound healing, as well as tumorigenesis and metastasis[240][241][242][243]. Thrombin-induced platelet activation is enhanced in the case of erosion and rupture of atherosclerotic plaques and in percutaneous coronary intervention, causing arterial thrombosis, the main cause of myocardial infarction and ischemic stroke.…”

“…Thrombin-induced platelet activation is enhanced in the case of erosion and rupture of atherosclerotic plaques and in percutaneous coronary intervention, causing arterial thrombosis, the main cause of myocardial infarction and ischemic stroke. Thrombin exerts its effects on platelets through PAR1 and PAR4, coupled to different types of G-proteins (Gi/o, Gq/11 and G12/13), as well as through β-arrestin pathways, and the activating effect of thrombin on platelet aggregation is realized mainly through Gq/11-proteins[241,243,244,245]. After Gq/11-mediated activation of PLCβ in platelets, the level of intracellular calcium increases and diacylglycerol-sensitive isoforms of protein kinase C is activated, which leads to activation of αIIb/β3-integrins, their translocation to the plasma membrane, and increased platelet aggregation.…”