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, respo ...
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 ba ...
.
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
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
; 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
The C5a receptor also known as complement component 5a receptor 1 (C5AR1) or CD88 (Cluster of Differentiation 88) is a G protein-coupled receptor for C5a. It functions as a complement receptor. C5a receptor modulates inflammatory responses, ob ...
(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 transcriptase, reverse transcription of an mRNA trans ...
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
paralog
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 spec ...
s, based on
phylogenetic analysis
In biology, phylogenetics (; from Greek φυλή/ φῦλον [] "tribe, clan, race", and wikt:γενετικός, γενετικός [] "origin, source, birth") is the study of the evolutionary history and relationships among or within groups o ...
, 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 spec ...
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
A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving ...
.
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 infl ...
,
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
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...
.
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
Cathepsin D is a protein that in humans is encoded by the ''CTSD'' gene. This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathe ...
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
Humanin is a micropeptide encoded in the mitochondrial genome by the 16S ribosomal RNA gene, MT-RNR2. Its structure contains a three-turn α-helix, and no symmetry.
In ''in vitro'' and animal models, it appears to have cytoprotective effects. ...
and thereby may be involved in inhibiting the inflammation occurring in and perhaps contributing to
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, 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 short-term me ...
.
See also
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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 ...
*
Formyl peptide receptor 2
N-formyl peptide receptor 2 (FPR2) is a G-protein coupled receptor (GPCR) located on the surface of many cell types of various animal species. The human receptor protein is encoded by the ''FPR2'' gene and is activated to regulate cell function b ...
*
N-Formylmethionine-leucyl-phenylalanine
''N''-Formylmethionyl-leucyl-phenylalanine (fMLF, fMLP or ''N''-formyl-met-leu-phe) is an ''N''- formylated tripeptide and sometimes simply referred to as chemotactic peptide is a potent polymorphonuclear leukocyte (PMN) chemotactic factor and ...
References
Further reading
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External links
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{{G protein-coupled receptors, g1
G protein-coupled receptors
Formyl peptide receptors