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.

Fig. 1

Mechanisms of PAR activation. PAR activation is regulated by a direct proteolytic cleavage at the N-terminus, b homo- or heterodimerization with other PARs and transactivation through the cleaved tethered ligand, c compartmentalization on the cell surface, d degradation or recycling by endosomal trafficking, e posttranslational modifications such as glycosylation, phosphorylation, and ubiquitination, and f co-localization with other receptors and cofactors

Fig. 2

Proteolytic PAR cleavage. a N-terminal sequences of human PARs (PAR1–4) containing potential cleavage sites. b Proteolytic cleavage of PARs by soluble exogenous proteases exposes new N-terminal sequences that serve as tethered ligands for G protein dependent activation of receptors. Alternatively, proteolytic cleavage at other sites destroys the function of the receptor to prevent intracellular signal transduction

Fig. 3

Non-mammalian exogenous proteases induce PAR-driven pathological effects. Various proteases are secreted from bacteria, amoebae, insects, plants, fungi, and snakes, and can cleave PARs and modulate signal transduction, leading to inflammation, thrombosis, or pain

Fig. 4

G protein-coupled signaling induced by PAR activation. Depending on the tethered ligand, activated PAR couples with G protein α-subtypes. Gαq activates phospholipase Cβ (PLCβ), which mobilizes calcium. This further activates MAPKs (ERK1/2) and induces Ras signaling. Primarily, Gα12/12 and Gaq activate the Rho pathway. Gαi inhibits the activation of adenylyl cyclase, which leads to reduced production of cAMP. In contrast, the βγ-subunit functions as a negative regulator when bound to the α-subunit. After receptor activation, subunits separate, and the βγ-subunit interacts with other proteins, thereby activating or inhibiting signaling

Fig. 5

PAR trafficking. Activation-independent constitutive or agonist-induced internalization regulates PAR1 signaling

Fig. 6

PAR modulators. Pharmacological substances, such as 1) peptides and peptidomimetics, 2) blocking antibodies, 3) small molecules, 4) pepducins, and 5) parmodulins are used as therapeutic agents that affect PAR activities