page_title: Protease-activated receptor
section_title: Activation
hierarchical_section_title: Protease-activated receptor / Activation
caption_attribution_description: English: Protease cuts the N-terminal sequence of PAR that exposes a new N-terminal sequence functions as a tethered ligand, which bind a conserved region on extracellular loop 2 (ECL2). Such bound causes the specific change in conformation of the PAR and alters the affinity for intracellular G-protein.
context_page_description: 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, myocytes and neurons.
context_section_description: Protease activated receptors are integral membrane proteins that are coupled to G-proteins and are activated by specific 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 (ECL2). Such bound causes the specific change in conformation of the  PAR and alters the affinity for intracellular G-protein. Four types of PAR receptors have been identified by molecular cloning, and classified according to the main enzyme that is able to activate it. It has been determined that a large group of proteases cleave and activate PARs receptors, including various endogenous proteases from: a) 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. Although the proteolysis is the main mechanism for PAR activation, it is well known that a synthetic peptide (SLIGKV) 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 (acts on PARs 1, 3 and 4) and trypsin (PAR 2). 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 (cAMP inhibitory), 12/13 (Rho and Ras activation) and q (calcium signalling) to cause cellular actions.
caption: Signal transduction by activation of PAR
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