N-formyl peptide receptor 3 (FPR3) is a receptor

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''FPR3''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

Nomenclature note

Confusingly, there are two nomenclatures for FPR receptors and their genes, the first one used, FPR, FPR1, and FPR2 and its replacement (which corresponds directly to these three respective receptors and their genes), FPR1, FPR2, and FPR3. The latter nomenclature is recommended by the International Union of Basic and Clinical Pharmacology and is used here. Other previously used names for FPR1 are NFPR, and FMLPR; for FPR2 are FPRH1, FPRL1, RFP, LXA4R, ALXR, FPR2/ALX, HM63, FMLPX, and FPR2A; and for FPR3 are FPRH2, FPRL2, and FMLPY.

FPR3 function

The overall function of FPR3 is quite unclear. Compared to FPR1 and FPR2, FPR3 is highly phosphorylated (a signal for receptor inactivation and internalization) and more localized to small intracellular vesicles. This suggests that FPR3 rapidly internalizes after binding its ligands and thereby may serve as a "decoy" receptor to reduce the binding of its ligands to FRP1 and FRP2 receptors.

Genes

Humans

The ''FPR3'' gene was cloned and named based on the similarity of the amino acid sequence which it encodes to that encoded by the gene for FPR1 (see

formyl peptide receptor 1 Formyl peptide receptor 1 (FPR1, FPR1 receptor, fMet-Leu-Phe receptor 1, FMLP receptor 1, or N-formylmethionyl-leucyl-phenylalanine receptor 1) is a cell surface receptor protein that in humans is encoded by the ''formyl peptide receptor 1'' (''F ...

for details) The studies indicated that FPR3 is composed of 352 amino acids and its gene, similar to ''FPR1'', has an intronless open reading frames which encodes a protein with the 7 transmembrane structure of G protein coupled receptors; FPR3 has 69% and 72% amino acid sequence identities with FPR1. All three genes localize to chromosome 19q.13.3 in the order of FPR1 (19q13.410), FPR2 (19q13.3-q13.4), and FPR3 (19q13.3-q13.4) to form a cluster which also includes the genes for another G protein-coupled chemotactic factor receptor, the C5a receptor (also termed CD88) and GPR77, and a second C5a receptor, C5a2 (C5L2), which has the structure of a G protein coupled receptor but fails to couple to G proteins and is of debated function.

Mice

Mouse FPR receptors localize to chromosome 17A3.2 in the following order: ''Fpr1'', ''Fpr-rs2'' (or ''fpr2''), ''Fpr-rs1'' (or ''LXA4R''), ''Fpr-rs4'', ''Fpr-rs7, Fpr-rs7'', ''Fpr-rs6'', and ''Fpr-rs3'';

Pseudogene Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Most arise as superfluous copies of functional genes, either directly by DNA duplication or indirectly by reverse transcription of an mRNA transcript. Pseudogenes ar ...

s ''ψFpr-rs2'' and ''ψFpr-rs3'' (or ''ψFpr-rs5'') lie just after Fpr-rs2 and Fpr-rs1, respectively. All of the active mouse FPR receptors have ≥50% amino acid sequence identity with each other as well as with the three human FPR receptors. Based on its predominantly intracellular distribution, mFpr-rs1 correlates, and therefore may share functionality, with human FPR3; However, the large number of mouse compared to human FPR receptors makes it difficult to extrapolate human FPR functions based on genetic (e.g. gene knockout or forced overexpression) or other experimental manipulations of the FPR receptors in mice.

Other species

FPR receptors are widely distributed throughout mammalian species with the FPR1, FPR2, and FPR3 paralogs, based on phylogenetic analysis, originating from a common ancestor and early duplication of FPR1 and FPR2/FPR3 splitting with FPR3 originating from the latest duplication event near the origin of primates. Rabbits express an

ortholog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a s ...

of FPR1 (78% amino acid sequence identity) with high binding affinity for FMLP; rats express an ortholog of FPR2 (74% amino acid sequence identity) with high affinity for lipoxin A4.

Cellular and tissue distribution

FPL3 is expressed by circulating

monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...

eosinophils Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...

, and

basophils Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammator ...

but not neutrophils; tissue

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

and dendritic cells.

Ligands and potential ligand-based disease related activities

The functions of FPR3 and the few ligands which activate it have not been fully clarified. Despite its homology to FPR1, FPR3 is unresponsive to many FPR1-stimulating formyl peptides including FMLP. However, fMMYALF, a N-formyl hexapeptide derived from the mitochondrial protein,

NADH dehydrogenase NADH dehydrogenase is an enzyme that converts nicotinamide adenine dinucleotide (NAD) from its reduced form (NADH) to its oxidized form (NAD+). Members of the NADH dehydrogenase family and analogues are commonly systematically named using the for ...

subunit 6, is a weak agonist for FPR3 but >100-fold more potent in stimulating FPR1 and FPR2. F2L is a naturally occurring acylated peptide derived from the N-terminal sequence of heme-binding protein 1 by cathepsin D cleavage that potently stimulates chemotaxis through FPR3 in monocytes and monocyte-derived dendritic cells. F2L thereby may be a pro-inflammatory stimulus for FPR3. Similar to FPR2 (see FPR2 section), FPR3 is activated by humanin and thereby may be involved in inhibiting the inflammation occurring in and perhaps contributing to

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

References

External links

* {{G protein-coupled receptors, g1 G protein-coupled receptors Formyl peptide receptors