Protease-activated receptor
Protease-activated receptors are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, and also on endothelial cells, fibroblasts, immune cells, myocytes, neurons, and tissues that line the gastrointestinal tract.
Protease-activated receptors, or PARs, are not to be mistaken with PAR proteins, a group of regulators of cellular polarity named after their associated partitioning phenotype.
Classification
There are four mammalian members of the protease-activated receptor family: PAR1 – encoded by the gene F2R, PAR2 – F2RL1, PAR3 – F2RL2 and PAR4 – F2RL3, each of these genes has its locus on chromosome 5 except that of PAR4, which is on chromosome 19. The protease specificities, expression patterns, and functions of each PAR vary across a range of tissues and cell types. They are also members of the seven-transmembrane G-protein-coupled receptor superfamily, and are expressed throughout the body.History
When scientists were researching the process of blood clotting in the late 1980s, they made the discovery of protease-activated receptors. A novel protein that was activated by thrombin, a crucial part of the clotting cascade, was discovered by a research team at the University of California, San Francisco in 1991. The team was directed by Shaun Coughlin. This protein, which was eventually given the designation protease-activated receptor 1, was the first to be recognized as a member of the PAR family.A second thrombin-activated protein, later known as PAR3, was identified in 1994. Later research revealed that PAR3 works as a cofactor for PAR4 but lacks a useful intracellular domain. A third member of the PAR family, known as PAR2, was discovered as a protein triggered by in 1996.
Activation
Protease activated receptors are integral membrane proteins that are coupled to G-proteins and are activated by proteolytic cleavage of the amino terminal sequence that exposes a new N-terminal sequence functions as a tethered ligand, which bind a conserved region on extracellular loop 2 the coagulation cascade, b) inflammatory cells, and c) the digestive tract. On the other hand, PARs can be specifically cleaved and irreversibly activated even by exogenous proteases originated from insects, bacteria or plants and fungi. The wide distribution of PARs in a variety of cells supports the idea that they are involved in many process related with the gastrointestinal physiology and cardiovascular physiology. Although the proteolysis is the main mechanism for PAR activation, it is well known that a synthetic peptide that mimics the new N-terminal sequence produced after the cleavage, activates PAR-2 receptors without its proteolytic processing. In this sense, here we report that TFF3 isolated from human breast milk activates PAR-2 receptors of intestinal epithelial cells HT-29. These findings suggest that TFF3 activates intestinal epithelial cells through G-protein-coupled PAR-2, and could actively participate in the immune system of breastfed babies inducing the production of peptides related to innate defense, such as defensins and cytokines.PARs are activated by the action of serine proteases such as thrombin and trypsin. These enzymes cleave the N-terminus of the receptor, which in turn acts as a tethered ligand. In the cleaved state, part of the receptor itself acts as the agonist, causing a physiological response.
Most of the PAR family act through the actions of G-proteins i, 12/13 and q to cause cellular actions.