F2RL1 gene

The F2RL1 gene (F2RL1 stands for: F2R Like Trypsin Receptor 1), also known as the PAR2 gene, is a protein-coding gene located on chromosome 5q13.3. An important paralog of this gene is F2R.

This gene encodes a member of the G protein-coupled receptor 1 protein family (PAR family). The encoded cell surface receptor is activated by proteolytic cleavage of its extracellular amino terminus, resulting in a new amino terminus that acts as a bound ligand that binds to an extracellular loop domain. Activation of the receptor has been shown to stimulate vascular smooth muscle relaxation, dilate blood vessels, increase blood flow and lower blood pressure. This protein also plays an important role in the inflammatory response and in innate and adaptive immunity.

The encoded protein is a receptor for trypsin and trypsin-like enzymes that is coupled to G proteins (Cheng RKY et al. 2017). Its function is mediated by the activation of various signaling pathways, including phospholipase C (PLC), intracellular calcium, mitogen-activated protein kinase (MAPK), I-kappaB kinase/NF-kappaB and Rho (Cheng RKY et al. 2017). Can also be transactivated by cleaved F2R/PAR1. Involved in the modulation of inflammatory responses and regulation of innate and adaptive immunity and acts as a sensor for proteolytic enzymes produced during infection. Generally has pro-inflammatory effects. May act synergistically with TLR4 and probably TLR2 in inflammatory responses and modulates TLR3 signaling. Plays a protective role in endothelial barrier formation; activity involves coagulation factor X. Regulates endothelial cell barrier integrity during neutrophil extravasation, probably after proteolytic cleavage by PRTN3 (Kuckleburg CJ et al 2013). Presumably plays a bronchoprotective role in the airway epithelium, but has also been shown to impair the airway epithelial barrier by disrupting E-cadherin adhesion (Cocks TM et al 1999).

Involved in the regulation of vascular tone; activation leads to hypotension, presumably mediated by vasodilation. Associated with a subset of G-protein alpha subunits such as GNAQ, GNA11, GNA14, GNA12 and GNA13, but probably not with G(o)-alpha, G(i) subunit alpha-1 and G(i) subunit alpha-2.

Presumed to be a class B receptor that is internalized as a complex with arrestin and migrates with it into endosomal vesicles, presumably as a desensitized receptor, for prolonged periods of time. Mediates inhibition of TNF-alpha-stimulated JNK phosphorylation by coupling to GNAQ and GNA11; function involves dissociation of RIPK1 and TRADD from TNFR1. Mediates phosphorylation of the RELA subunit of nuclear factor NF-kappa-B at Ser-536; function involves IKBKB and is predominantly independent of G proteins. Involved in cellular migration. Involved in cytoskeletal remodeling and chemotaxis through beta-arrestin-promoted scaffolding; function is independent of GNAQ and GNA11 and involves promotion of cofilin dephosphorylation and actin filament severing. Induces the redistribution of COPS5 from the plasma membrane to the cytosol, and activation of the JNK cascade is mediated by COPS5. Involved in the recruitment of leukocytes to sites of inflammation and is the main PAR receptor that can modulate eosinophil function, such as secretion of proinflammatory cytokines, superoxide production and degranulation. During inflammation, it promotes the maturation of dendritic cells, transport to the lymph nodes and the subsequent activation of T cells. Participates in the antimicrobial response of innate immune cells; activation promotes phagocytosis of Gram-positive and killing of Gram-negative bacteria. Acts synergistically with interferon-gamma in enhancing antiviral responses. Plays a role in a number of acute and chronic inflammatory diseases, e.g. of the joints, lungs, brain, gastrointestinal tract, periodontium, skin and vascular system, as well as in autoimmune diseases.

There is evidence of a correlation between sensitivity to cold pain and the rs2243057 polymorphism of the PAR2/F2RL1 gener. There is also a correlation between sensitivity to cold and the s12992084 polymorphism of the TRPM8 gene. It can be assumed that genetic polymorphisms of both PAR2/F2RL1 and TRPM8 are involved in the individual differences in sensitivity to cold pain (Soeda M et al. 2021)

Diseases associated with F2RL1 include irritable bowel syndrome and dipsogenic diabetes insipidus. Related signaling pathways include class A/1 (rhodopsin-like receptors) and GPCR downstream signaling.

Protease-activated receptors (PARs - also known as thrombin receptors) are G-protein-coupled receptors that are activated by cleavage of their N-terminal domains by serine proteases. Hydrolysis exposes a bound peptide ligand that influences transmembrane signaling.

There is evidence of a correlation between sensitivity to cold pain and the rs2243057 polymorphism of the PAR2/F2RL1 gene. Furthermore, there is a correlation between sensitivity to cold and the rs12992084 polymorphism of the TRPM8 gene. It can be assumed that genetic polymorphisms of both PAR2/F2RL1 and TRPM8 are involved in the individual differences in sensitivity to cold pain (Soeda M et al. 2021)

1. Cheng RKY et al. (2017) Structural insight into allosteric modulation of protease-activated receptor 2. Nature 545:112-115.
2. Kuckleburg CJ et al. (2013) Neutrophil proteinase 3 acts on protease-activated receptor-2 to enhance vascular endothelial cell barrier function. Arterioscler Thromb Vasc Biol 33:275-284.
3. Soeda M et al. (2021) Cold pain sensitivity is associated with single-nucleotide polymorphisms of PAR2/F2RL1 and TRPM8. Mol Pain 17:17448069211002009.