Formyl peptide receptor

protein
Name=formyl peptide receptor 1
caption=


width=
HGNCid=3826
Symbol=FPR1
AltSymbols=
EntrezGene=2357
OMIM=136537
RefSeq=NM_002029
UniProt=P21462
PDB=
ECnumber=
Chromosome=19
Arm=q
Band=13.41
LocusSupplementaryData=protein
Name = formyl peptide receptor-like 1
caption =


width =
HGNCid = 3827
Symbol = FPRL1
AltSymbols =
EntrezGene = 2358
OMIM = 136538
RefSeq = NM_001462
UniProt = P25090
PDB =
ECnumber =
Chromosome = 19
Arm = q
Band = 13.3-13.4
LocusSupplementaryData = protein
Name = formyl peptide receptor-like 2
caption =


width =
HGNCid = 3828
Symbol = FPRL2
AltSymbols =
EntrezGene = 2359
OMIM = 136539
RefSeq = NM_002030
UniProt = P25089
PDB =
ECnumber =
Chromosome = 19
Arm = q
Band = 13.3-13.4
LocusSupplementaryData =

The formyl peptide receptors (FPR) are a members of a class of G protein-coupled receptors involved in chemotaxis.cite journal | author = Migeotte I, Communi D, Parmentier M | title = Formyl peptide receptors: a promiscuous subfamily of G protein-coupled receptors controlling immune responses | journal = Cytokine Growth Factor Rev. | volume = 17 | issue = 6 | pages = 501–19 | year = 2006 | pmid = 17084101 | doi = 10.1016/j.cytogfr.2006.09.009 | issn = ] 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.cite journal | author = Le Y, Murphy PM, Wang JM | title = Formyl-peptide receptors revisited | journal = Trends Immunol. | volume = 23 | issue = 11 | pages = 541–8 | year = 2002 | pmid = 12401407 | doi = 10.1016/S1471-4906(02)02316-5 | issn = ] cite journal | author = Panaro MA, Acquafredda A, Sisto M, Lisi S, Maffione AB, Mitolo V | title = Biological role of the N-formyl peptide receptors | journal = Immunopharmacology and immunotoxicology | volume = 28 | issue = 1 | pages = 103–27 | year = 2006 | pmid = 16684671 | doi = 10.1080/08923970600625975 | issn = ] 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.cite journal | author = Braun MC, Wang JM, Lahey E, Rabin RL, Kelsall BL | title = Activation of the formyl peptide receptor by the HIV-derived peptide T-20 suppresses interleukin-12 p70 production by human monocytes | journal = Blood | volume = 97 | issue = 11 | pages = 3531–6 | year = 2001 | pmid = 11369647 | doi = 10.1182/blood.V97.11.3531 | issn = ]

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.cite journal | author = Lala A, Gwinn M, De Nardin E | title = Human formyl peptide receptor function role of conserved and nonconserved charged residues | journal = Eur. J. Biochem. | volume = 264 | issue = 2 | pages = 495–9 | year = 1999 | pmid = 10491096 | doi = 10.1046/j.1432-1327.1999.00647.x | issn = ]

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.cite journal | author = 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 | title = 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 | journal = Nat. Med. | volume = 7 | issue = 11 | pages = 1209–16 | year = 2001 | pmid = 11689885 | doi = 10.1038/nm1101-1209 | issn = ]

References

ee also

* Chemotaxis Receptors

External links

* [http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1359 IUPHAR GPCR Database - Formylpeptide receptors]
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