Diversification of PAR signaling through receptor crosstalk

Abstract

Protease activated receptors (PARs) are among the first receptors shown to transactivate other receptors: noticeably, these interactions are not limited to members of the same family, but involve receptors as diverse as receptor kinases, prostanoid receptors, purinergic receptors and ionic channels among others. In this review, we will focus on the evidence for PAR interactions with members of their own family, as well as with other types of receptors. We will discuss recent evidence as well as what we consider as emerging areas to explore; from the signalling pathways triggered, to the physiological and pathological relevance of these interactions, since this additional level of molecular cross-talk between receptors and signaling pathways is only beginning to be explored and represents a novel mechanism providing diversity to receptor function and play important roles in physiology and disease.

Airborne indoor allergen serine proteases and their contribution to sensitisation and activation of innate immunity in allergic airway disease

“…It has also been discovered that the T2 environment-derived cytokine response alters PAR-2 polarisation in human airway epithelial cells, therefore reducing tolerance to protease exposure and resulting in the promotion of allergic inflammation in the airway [ 157 ]. Even though it was initially suggested that G protein-coupled receptors function as solitary monomeric units, there is evidence that PARs can form dimers or can transactivate other types of receptors [ 189 ]. PAR-2 facilitates ROS signalling and has potential to transactivate receptor tyrosine kinases (RTKs) in the airways [ 190 ].…”

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

“…Regulatory effects mediated through PAR1 and PAR4 are determined by the ability of these receptors to form heterodimeric complexes with PAR2 and PAR3 [ 245 , 256 ]. In the case of PAR1, the formation of a heterodimeric complex with PAR2 provides PAR1-induced activation of PAR2 and stimulation of thrombin-mediated β-arrestin signaling, which significantly contributes to PAR-dependent effects on blood coagulation and inflammation [ 257 ].…”

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

“…A Regulatory effects mediated through PAR1 and PAR4 are determined by the ability of these receptors to form heterodimeric complexes with PAR2 and PAR3 [241,253]. In the case of PAR1, the formation of a heterodimeric complex with PAR2 provides PAR1induced activation of PAR2 and stimulation of thrombin-mediated β-arrestin signaling, which significantly contributes to PAR-dependent effects on blood coagulation and inflammation [254].…”