Formyl peptide receptor
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| Identifiers | |
| Symbol | FPR1 |
| Entrez | 2357 |
| HUGO | 3826 |
| OMIM | 136537 |
| RefSeq | NM_002029 |
| UniProt | P21462 |
| Other data | |
| Locus | Chr. 19 q13.41 |
| Identifiers | |
| Symbol | FPRL1 |
| Entrez | 2358 |
| HUGO | 3827 |
| OMIM | 136538 |
| RefSeq | NM_001462 |
| UniProt | P25090 |
| Other data | |
| Locus | Chr. 19 q13.3-13.4 |
| Identifiers | |
| Symbol | FPRL2 |
| Entrez | 2359 |
| HUGO | 3828 |
| OMIM | 136539 |
| RefSeq | NM_002030 |
| UniProt | P25089 |
| Other data | |
| Locus | Chr. 19 q13.3-13.4 |
The formyl peptide receptors (FPR) are a members of a class of G protein-coupled receptors involved in chemotaxis.[1] These receptors where originally identified by their ability to bind N-formyl peptides such as N-formylmethionine produced by the degradation of either bacterial or host cells.[2][3] Hence formyl peptide receptors are involved in mediating immune cell response to infection. These receptors may also act to suppress the immune system under certain conditions.[4]
Contents |
[edit] Structure - function
The formyl peptide receptor (FPR) belongs to the class of serpentine receptors, possessing seven hydrophobic transmembrane domains. The conformation of the FPR is stabilized by several interactions. These include potential salt bridge formation between Arg84-Arg205, Lys85-Arg205, and Lys85-Asp284 which help determine the three-dimensional structure of transmembrane domains, as well as positively charged residues (Arg, Lys) which interact with negatively charged phosphates. Furthermore residue Arg163 may interact with the ligand binding pocket of the second extracellular loop of the FPR. With respect to binding of the formyl Met-Leu-Phe peptide, there are additional potential interactions which include hydrogen bonding interactions between Arg84 and Lys85 of the first extracellular loop and the N-formly group of the ligand as well as the peptide backbone of formyl Met-Leu-Phe which can form similar interactions. The formyl-Met moiety of the ligand was shown to form disulfide bridges with Cys residues, and an interaction with Arg163 was also demonstrated. (It is important to mention that some interaction which stabilize the conformation of the receptor may also influence ligand-binding.) Some oligopeptides were also described as characteristic constituents linked to Asn-s of the extracellular N terminal part and to the ligand binding pocket of the second extracellular loop. These components can also determine or make more specific the ligand-receptor interaction.[5]
[edit] Signaling pathways
Induction of FPR triggers multiple changes in eukaryotic cells including rearrangement of the cytoskeleton which in turn facilitates cell migration and the synthesis of chemokines. Important FPR regulated pathways include:
- G protein dependent activation of phospholipase C (PLC) which results in the breakdown of the membrane constituent phospholipid, phosphatidylinositol (4,5)-bisphosphate (PIP2) into phosphatidylinositol (3,4,5)-trisphosphate (IP3) and diacyl glycerol (DAG). IP3 is one of the most effective inducer of Ca2+ increase from cytoplasmic pools and from outside the cell via opening Ca2+ channels. DAG in turn is an inducer of protein kinase C (PKC).
- Activation of the regulatory small GTPase, RAS. The active RAS can in turn activate RAF, a Ser/Thr kinase. In the next step mitogen-activated protein kinases (MAP kinases) are activated. (Also known as extracellular signal-regulated kinases - ERKs or MAP/ERK kinase (MEK)). As a result of the last step, ERK1 and ERK2 are activated. The phosphorylated forms of ERKs can continue the cascade by triggering activation more interacting kinases which results in altered transcriptional activity in the nucleus.
- Ligand binding to FPR can also induce the activation of CD38, an ectoenzyme of the surface membrane. As a result of activation NAD+ molecules will enter the cytoplasm. NAD+ is converted into cyclic ADP ribose (cADPR), a second messenger which interacts with ryanodine receptors (RyR) on the surface of the rough endoplasmic reticulum. The overal result of the process is increased cytoplasmic Ca2+ levels via the direct pathway described above and also via indirect pathways such as opening of Ca2+ channels in the cell membrane. The sustained increase of Ca2+ is required for directed migration of the cells.[6]
[edit] References
- ^ Migeotte I, Communi D, Parmentier M (2006). "Formyl peptide receptors: a promiscuous subfamily of G protein-coupled receptors controlling immune responses". Cytokine Growth Factor Rev. 17 (6): 501–19. doi:. PMID 17084101.
- ^ Le Y, Murphy PM, Wang JM (2002). "Formyl-peptide receptors revisited". Trends Immunol. 23 (11): 541–8. doi:. PMID 12401407.
- ^ Panaro MA, Acquafredda A, Sisto M, Lisi S, Maffione AB, Mitolo V (2006). "Biological role of the N-formyl peptide receptors". Immunopharmacology and immunotoxicology 28 (1): 103–27. doi:. PMID 16684671.
- ^ Braun MC, Wang JM, Lahey E, Rabin RL, Kelsall BL (2001). "Activation of the formyl peptide receptor by the HIV-derived peptide T-20 suppresses interleukin-12 p70 production by human monocytes". Blood 97 (11): 3531–6. doi:. PMID 11369647.
- ^ Lala A, Gwinn M, De Nardin E (1999). "Human formyl peptide receptor function role of conserved and nonconserved charged residues". Eur. J. Biochem. 264 (2): 495–9. doi:. PMID 10491096.
- ^ Partida-Sánchez S, Cockayne DA, Monard S, Jacobson EL, Oppenheimer N, Garvy B, Kusser K, Goodrich S, Howard M, Harmsen A, Randall TD, Lund FE (2001). "Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo". Nat. Med. 7 (11): 1209–16. doi:. PMID 11689885.
[edit] See also
[edit] External links
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