Proteinase-activated receptor-2 in the skin: receptor expression, activation and function during health and disease

Proteinase-activated receptors (PARs) are G-protein-coupled receptors with seven transmembrane domains that are activated by specific proteolytic cleavage of the extracellular N-terminus. To date, four PARs are known (PAR(1-4)). They are stimulated by a variety of serine proteinases. PAR(1), PAR(3) and PAR(4) are cleaved by thrombin. Both PAR(1) and PAR(4) can be activated by trypsin as well; and PAR1 can also be activated by matrix metalloproteinase-1. PAR(2) can be activated by a variety of endogenous serine proteinases with trypsin-like specificity. However, the receptor can additionally be stimulated by various proteinases produced by pathogenic organisms. It can also be inactivated by certain proteinases. PAR(2) is expressed by many cell types present in the skin, including epidermal keratinocytes, fibroblasts, endothelial cells as well as by afferent neuron terminals. Moreover, functional PAR(2) is expressed by cells crucially involved in innate and adaptive immunity such as eosinophils, neutrophils, monocytes, macrophages, dendritic cells, mast cells and T cells. Activation of the receptor leads to the production of various cytokines and chemokines which modulate skin homeostasis, immune and inflammatory responses as well as tumor surveillance.