Alternative titles; symbols
HGNC Approved Gene Symbol: F2RL1
Cytogenetic location: 5q13.3 Genomic coordinates (GRCh38): 5:76,819,030-76,835,315 (from NCBI)
Proteinase-activated receptor-2 (PAR2) is a member of the large family of 7-transmembrane-region receptors that couple to guanine nucleotide-binding proteins (Nystedt et al., 1995).
Nystedt et al. (1994) cloned the mouse Par2 sequence from genomic DNA.
Nystedt et al. (1995) cloned the human PAR2 gene. The deduced 397-amino acid protein contains an N-terminal signal peptide and 7 transmembrane domains. Human PAR2 shares 83% amino acid identity with the 399-amino acid mouse Par2 protein. Northern blot analysis showed that the PAR2 transcript was widely expressed in human tissues, with especially high levels in pancreas, liver, kidney, small intestine, and colon. Moderate expression was detected in many organs, but no expression was found in brain or skeletal muscle.
Nystedt et al. (1994) found that, when expressed in frog oocytes, mouse Par2 could be activated with nanomolar concentrations of the serine protease trypsin (276000) but not with thrombin (176930) in doses up to 100 nM.
Nystedt et al. (1995) found that, when expressed in Chinese hamster ovary cells, human PAR2 responded to trypsin and a peptide from the receptor sequence. Nystedt et al. (1995) found that the physiologic activator at PAR2 was apparently not activated by ordinary ligand binding but by proteolytic cleavage of its extracellular N terminus. The cleavage left the new amino terminus, a tethered ligand, free to interact with some other region of the receptor, presumably to effect receptor activation. Nystedt et al. (1995) noted that PAR2 shares this special mode of activation with thrombin receptor (F2R, or PAR1; 187930), for which this mechanism was first described.
PAR2 is highly expressed in colon in epithelial and neuronal elements. Fiorucci et al. (2001) showed that PAR2 activation prevents the development and induces healing of T helper cell type 1-mediated experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. Protection exerted by PAR2 in TNBS-treated mice was reverted by injecting mice with a truncated form of calcitonin gene-related peptide (114130) and by ablation of sensory neurons with the neurotoxin capsaicin. Collectively, these studies showed that PAR2 is an antiinflammatory receptor in the colon and suggested that PAR2 ligands might be effective in the treatment of inflammatory bowel diseases (see 266600).
Ferrell et al. (2003) demonstrated that PAR2 plays a key role in chronic joint inflammation. Using an adjuvant monoarthritis mouse model of chronic inflammation, they found that expression of PAR2 was substantially upregulated in inflamed tissues. Proinflammatory effects such as prolonged joint swelling and synovial hyperemia were also induced by PAR2 agonists. Consistent with this, PAR2-deficient mice had no joint swelling and virtually no histologic evidence of joint damage after the administration of the adjuvant, whereas heterozygous mice showed an intermediate phenotype.
Dai et al. (2007) provided evidence for a mechanism in which the proteases trypsin or tryptase (191080) activate PAR2, which in turn sensitizes the TRPA1 (604775) channel. Trpa1 and Par2 colocalized in primary afferent neurons within rat dorsal root ganglia, and patch-clamp studies in HEK293 cells showed that PAR2 agonists increased TRPA1 currents. The increased sensitivity of TRPA1 was due to phospholipase C (see 172420), which hydrolyzes plasma membrane phosphatidylinositol-4,5-bisphosphate (PIP2) and thus releases PIP2-mediated inhibition of TRPA1. Studies in rats showed that AITC- or cinnamaldehyde-evoked pain behavior was enhanced by Par2 activation in vivo.
Pepducins are lipid-conjugated, membrane-tethered, cell-penetrating peptides that act as agonists or antagonists of their cognate receptor. Kaneider et al. (2007) found that pepducin antagonists and agonists based on the third intracellular loop of PAR1 had substantial beneficial or harmful effects on survival, vascular integrity, and disseminated intravascular coagulation in mice depending on the stage of sepsis. The effects of the pepducins were lost in Par1-deficient mice. RNA interference-mediated suppression of PAR2 expression in human endothelial cells showed that the protective effects of PAR1 activation required PAR2. Transactivation of PAR2 signaling by PAR1 was enhanced by endotoxin-dependent recruitment of PAR1-PAR2 complexes to the endothelial cell surface. Kaneider et al. (2007) proposed that therapeutics that selectively activate PAR1-PAR2 complexes may be beneficial in the treatment of sepsis.
Ghorpade et al. (2018) showed that obesity in mice stimulates hepatocytes to synthesize and secrete dipeptidyl peptidase-4 (DPP4; 102720), which acts with plasma factor Xa (see 613872) to inflame adipose tissue macrophages. Silencing expression of DPP4 in hepatocytes suppressed inflammation of visceral adipose tissue and insulin resistance; however, a similar effect was not seen with the orally administered DPP4 inhibitor sitagliptin. Inflammation and insulin resistance were also suppressed by silencing expression of caveolin-1 (601047) or PAR2 in adipose tissue macrophages; these proteins mediate the actions of DPP4 and factor Xa, respectively. Ghorpade et al. (2018) concluded that hepatocyte DPP4 promotes visceral adipose tissue inflammation and insulin resistance in obesity, and that targeting this pathway may have metabolic benefits that are distinct from those observed with oral DPP4 inhibitors.
Nystedt et al. (1995) determined that the F2RL1 gene contains 2 exons separated by about 14 kb. Exon 1 encodes 27 amino acids, and exon 2 encodes the remainder of the protein.
By fluorescence in situ hybridization, Nystedt et al. (1995) mapped the PAR2 gene to chromosome 5q13. They noted that the thrombin receptor gene (F2R) also maps to 5q13, raising questions concerning the evolution of proteinase-activated receptors.
Badeanlou et al. (2011) found that tissue factor (TF) (F3; 134390) activity was upregulated in plasma and epididymal visceral adipose tissue extracts in mice fed a high-fat diet. Mutant mice lacking the cytoplasmic domain of Tf (Tf-delta-CT mice) or deficient in Par2 expression (Par2 -/- mice) gained less weight than wildtype mice when fed a high-fat diet. Tf-delta-CT or Par2 -/- mice also had lower plasma concentrations of free fatty acids and fasting insulin and glucose, with improved insulin sensitivity and glucose tolerance, compared with wildtype mice fed a high-fat diet. Tf-delta-CT Par2 -/- double-mutant mice showed no additive effects. In hematopoietic cells, ablation of Tf/Par2 signaling reduced adipose tissue macrophage inflammation, and specific inhibition of macrophage Tf signaling ameliorated insulin resistance. In nonhematopoietic cells, Tf/activated factor VII (F7; 613878)/Par2 signaling promoted obesity.
Badeanlou, L., Furlan-Freguia, C., Yang, G., Ruf, W., Samad, F. Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation. Nature Med. 17: 1490-1497, 2011. [PubMed: 22019885] [Full Text: https://doi.org/10.1038/nm.2461]
Dai, Y., Wang, S., Tominaga, M., Yamamoto, S., Fukuoka, T., Higashi, T., Kobayashi, K., Obata, K., Yamanaka, H., Noguchi, K. Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. J. Clin. Invest. 117: 1979-1987, 2007. Note: Erratum: J. Clin. Invest. 117: 3140 only, 2007. [PubMed: 17571167] [Full Text: https://doi.org/10.1172/JCI30951]
Ferrell, W. R., Lockhart, J. C., Kelso, E. B., Dunning, L., Plevin, R., Meek, S. E., Smith, A. J. H., Hunter, G. D., McLean, J. S., McGarry, F., Ramage, R., Jiang, L., Kanke, T., Kawagoe, J. Essential role for proteinase-activated receptor-2 in arthritis. J. Clin. Invest. 111: 35-41, 2003. [PubMed: 12511586] [Full Text: https://doi.org/10.1172/JCI16913]
Fiorucci, S., Mencarelli, A., Palazzetti, B., Distrutti, E., Vergnolle, N., Hollenberg, M. D., Wallace, J. L., Morelli, A., Cirino, G. Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis. Proc. Nat. Acad. Sci. 98: 13936-13941, 2001. [PubMed: 11717450] [Full Text: https://doi.org/10.1073/pnas.241377298]
Ghorpade, D. S., Ozcan, L., Zheng, Z., Nicoloro, S. M., Shen, Y., Chen, E., Bluher, M., Czech, M. P., Tabas, I. Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance. Nature 555: 673-677, 2018. [PubMed: 29562231] [Full Text: https://doi.org/10.1038/nature26138]
Kaneider, N. C., Leger, A. J., Agarwal, A., Nguyen, N., Perides, G., Derian, C., Covic, L., Kuliopulos, A. 'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage. Nature Immun. 8: 1303-1312, 2007. [PubMed: 17965715] [Full Text: https://doi.org/10.1038/ni1525]
Nystedt, S., Emilsson, K., Larsson, A.-K., Strombeck, B., Sundelin, J. Molecular cloning and functional expression of the gene encoding the human proteinase activated receptor 2. Europ. J. Biochem. 232: 84-89, 1995. [PubMed: 7556175] [Full Text: https://doi.org/10.1111/j.1432-1033.1995.tb20784.x]
Nystedt, S., Emilsson, K., Wahlestedt, C., Sundelin, J. Molecular cloning of a potential proteinase-activated receptor. Proc. Nat. Acad. Sci. 91: 9208-9212, 1994. [PubMed: 7937743] [Full Text: https://doi.org/10.1073/pnas.91.20.9208]