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PAF receptor

Family: Platelet-activating factor receptor

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Biologically Significant Variants
General Comments
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 342 1p35-p34.3 PTAFR platelet-activating factor receptor 8,30,40,49,53
Mouse 7 341 D2.2 Ptafr platelet-activating factor receptor 24
Rat 7 341 5q36 Ptafr platelet-activating factor receptor 6
Previous and Unofficial Names
Paf-acether receptor
AGEPC receptor
PAF-R
PAFr
platelet-activating factor receptor
Database Links
ChEMBL Target 251 (Hs), 10586 (Mm), 10587 (Rn)
Ensembl ENSG00000169403 (Hs), ENSMUSG00000056529 (Mm), ENSRNOG00000013231 (Rn)
Entrez Gene 5724 (Hs), 19204 (Mm), 58949 (Rn)
GeneCards PTAFR (Hs)
GenitoUrinary Development Molecular Anatomy Project Ptafr (Mm)
HomoloGene 20260 (Hs)
Human Protein Reference Database 01422 (Hs)
InterPro P25105 (Hs), Q62035 (Mm), P46002 (Rn)
KEGG Gene hsa:5724 (Hs), mmu:19204 (Mm), rno:58949 (Rn)
OMIM 173393 (Hs)
PharmGKB Gene PA33933 (Hs)
PhosphoSitePlus P25105 (Hs)
Protein Ontology (PRO) PRO:000001501 (Hs)
RefSeq Nucleotide NM_000952 (Hs), NM_001081211 (Mm), NM_053321 (Rn)
RefSeq Protein NP_000943 (Hs), NP_001074680 (Mm), NP_445773 (Rn)
TreeFam ENSG00000169403 (Hs), ENSMUSG00000056529 (Mm), ENSRNOG00000013231 (Rn)
UniGene Hs. 46 (Hs)
UniProt P25105 (Hs), Q62035 (Mm), P46002 (Rn)
Wikipedia PAF receptor
Platelet-activating factor receptor
Search for 3D structures on the PDB
Search by keyword: Platelet-activating factor receptor PAF receptor Search by accession number: P46002, P25105, Q62035
Natural/Endogenous Ligand(s)
mc-PAF
PAF
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[3H]PAF Hs Full agonist 8.8 – 8.9 pKd 18,40
PAF Hs Full agonist 7.5 – 7.9 pKi 40,43
PAF Hs Full agonist 8.2 pIC50 3
2-O-ethyl-PAF C-16 Hs Full agonist 7.7 pIC50 3
2-O-methyl-PAF C-18 Hs Full agonist 5.8 pIC50 3
enantio PAF C-16 Hs Full agonist 5.0 pIC50 3
Agonist Comments
Some oxidised phospholipids are also agonists at the PAF receptor [32,51], reviewed in [33].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[3H]52770 RP Hs Antagonist 8.4 pKd 34
[3H]apafant Hs Antagonist 7.4 – 8.0 pKd 3,18,40
SR 27417 Hs Antagonist 10.3 pKi 21
ABT-299 Hs Antagonist 9.5 pKi 1
ABT-491 Hs Antagonist 9.2 pKi 2
52770 RP Hs Antagonist 8.2 pKi 34
10-OBn-7α-F-gingkolide B Mm Antagonist 7.0 pKi 59
7α-Cl-ginkgolide B Mm Antagonist 7.0 pKi 59
10-OBn-ginkgolide B Mm Antagonist 6.9 pKi 59
BN 50739 Hs Antagonist 6.9 pKi 55
apafant Hs Antagonist 5.2 – 7.5 pKi 43,55
7α-N3-ginkgolide B Mm Antagonist 6.3 pKi 59
10-OBn-epi-ginkgolide C Mm Antagonist 6.2 pKi 59
7α-NHMe-ginkgolide B Mm Antagonist 6.2 pKi 59
ginkgolide B Mm Antagonist 6.1 – 6.2 pKi 52,59
7α-F-ginkgolide B Mm Antagonist 6.0 pKi 59
10-OBn-ginkgolide C Mm Antagonist 5.8 pKi 59
7α-NHEt-ginkgolide B Mm Antagonist 5.8 pKi 59
ginkgolide A Mm Antagonist 5.8 pKi 52
7α-OCOCH2Ph-ginkgolide B Mm Antagonist 5.6 pKi 59
7-epi-GC Mm Antagonist 5.4 pKi 59
7α-NH2-ginkgolide B Mm Antagonist 5.1 pKi 59
7α-OAc-ginkgolide B Mm Antagonist 5.1 pKi 59
ginkgolide J Mm Antagonist 5.0 pKi 52
ginkgolide C Mm Antagonist 4.9 pKi 52
Y-24180 Hs Antagonist 9.0 pIC50 40
CV-6209 Hs Antagonist 8.1 – 8.3 pIC50 19,40
SDZ 64-412 Hs Antagonist 7.2 pIC50 20
SCH 37370 Hs Antagonist 6.2 pIC50 29
SCH 40338 Hs Antagonist 6.2 pIC50 29
View species-specific antagonist tables
Antagonist Comments
The above binding assays were performed using transfected cells, except references [1-2,20] which measured binding to preparations of platelet membranes, reference [34] which measured binding to human polymorphonuclear leukocytes and reference [29] which measured the inhibition of platelet aggregation.

The above table lists a small selection of the known PAF receptor antagonists. For reviews on PAF receptor antagonists see [11,54].

ABT-299 is a prodrug of A-85783.
Primary Transduction Mechanisms
Transducer Effector/Response
Gq/G11 family Adenylate cyclase stimulation
References:  13
Secondary Transduction Mechanisms
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
References:  13
Tissue Distribution
Fallopian tubes.
Species:  Human
Technique:  RT-PCR and Western blotting.
References:  58
Bone marrow stromal cells.
Species:  Human
Technique:  RT-PCR.
References:  14
Spermatozoa (proximal head, midpiece >> distal head, tail).
Species:  Human
Technique:  Immunofluorescent microscopy.
References:  45
Dorsal root ganglion and spinal cord.
Species:  Mouse
Technique:  RT-PCR.
References:  36
Spleen > skeletal muscle, thioglycollate elicited macrophages > small intestine > resident peritoneal macrophages > lung > heart > liver > kidney > brain.
Species:  Mouse
Technique:  Northern blotting.
References:  24
Cerebral cortex (intense signals scattered randomly in all of the layers, moderate signals found in layers II-VI), olfactory bulb, hippocampus (intense signals scattered randomly, moderate signals found in the pyramidal cell layer and dentate gyrus), medial thalamus, hypothalamus, and cerebellum (intense signals were scattered randomly, slight to moderate signals were found in the granular cell and Purkinje cell layers).
Species:  Rat
Technique:  in situ hybridisation.
References:  35
Microglia.
Species:  Rat
Technique:  in situ hybridisation, Northen blotting and RT-PCR.
References:  35
Kidney: glomerulus > proximal convoluted tubule > proximal straight tubule > cortical collecting duct, outer medullary collecting duct, distal convoluted tubule > cortical thick ascending limb, medullary thick ascending limb.
Species:  Rat
Technique:  RT-PCR.
References:  4
Spleen > small intestine > kidney > lung > liver >> pancreas >> brain.
Species:  Rat
Technique:  Northern blotting.
References:  6
Pancreatic microvascular endothelial cells.
Species:  Rat
Technique:  Immunohistochemistry.
References:  17
Expression Datasets

Click here to show/hide data

Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of PLCβ3 activity in HUVECs.
Species:  Human
Tissue:  HUVECs.
Response measured:  PLCβ3 activation via Gαq upon application of agonist.
References:  13
Measurement of FAK (Focal Adhesion Kinase) activity in HUVECs.
Species:  Human
Tissue:  HUVECs.
Response measured:  FAK activation via Gαq upon application of an agonist.
References:  13
Measurement of membrane potential in Xenopus oocytes transfected with the human PAF recptor.
Species:  Human
Tissue:  Xenopus oocytes.
Response measured:  Production of an inward current upon application of an agonist.
References:  40
Measurement of IP3 levels in COS-7 cells transfected with the human PAF receptor.
Species:  Human
Tissue:  COS-7 cells.
Response measured:  Accumulation of IP3 upon application of an agonist.
References:  40
Measurement of membrane potential in Xenopus oocytes transfected with the human PAF receptor.
Species:  Human
Tissue:  Xenopus oocytes.
Response measured:  Production of a Ca2+-activated Cl- current upon application of an agonist.
References:  53
Measurement of membrane potential in Xenopus oocytes transfected with the rat PAF receptor.
Species:  Rat
Tissue:  Xenopus oocytes.
Response measured:  Cl- channel opening.
References:  6
Measurement of cAMP levels in Human Umbilical Vein Endothelial cells (HEVECs) endogenously expressing the PAF receptor.
Measurement of PKA activity and subsequent signalling to Src.
Species:  Human
Tissue:  HUVECs.
Response measured:  Increase in cAMP levels via Gαq, subsequent increase in PKA activity and signalling to Src, upon application of an agonist.
References:  13
Measurement of Ca2+ mobilisation in CHO cells transfected with the wild-type receptor or the Ala224 -> Asp substituted mutant PAF receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Equivalent Ca2+ mobilisation in both the wild-type and mutant receptors.
References:  18
Measurement of IP3 and cAMP levels in CHO cells transfected with the wild-type receptor or the Ala224 -> Asp substituted mutant PAF receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  IP3 production and inhibition of cAMP accumulation upon activation of the wild-type receptor. Both reduced with the mutant receptor.
References:  18
Measurement of chemotactic activity in CHO cells transfected with either the wild-type or the Ala224 -> Asp substituted mutant PAF receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Reduced chemotactic index with the mutant receptor.
References:  18
Measurement of Ca2+ levels in isolated rat microglial cells using fluorometric Ca2+ imaging.
Species:  Rat
Tissue:  Isolated microglia.
Response measured:  Elevated [Ca2+]i in response to PAF.
References:  35
Measurement of Ca2+ levels in cultured rat hippocampal cells using fluorometric Ca2+ imaging.
Species:  Rat
Tissue:  Cultured hippocampal cells.
Response measured:  Elevated [Ca2+]i in response to PAF.
References:  35
Measurement of arachidonic acid levels in isolated rat microglial cells endogenously expressing the PAF receptor.
Species:  Rat
Tissue:  Isolated microglia.
Response measured:  Arachidonic acid release is response to PAF.
References:  35
Physiological Functions
Vasodilation.
Species:  Rat
Tissue:  Mesenteric arterial bed.
References:  28
Superoxide production.
Species:  Human
Tissue:  Eosinophils.
References:  5
Cell proliferation, motility and angiogenic response.
Species:  Human
Tissue:  Breast cancer cells.
References:  7
Enhancement of excitatory synaptic transmission.
Species:  Rat
Tissue:  Cultured hippocampal neurons.
References:  10
PAF receptor activation may be an initiator of neuronal dysfunction and cell death involved with HIV-1 associated dementia.
Species:  Human
Tissue:  Primary neurons.
References:  44
Cell aggregation.
Species:  Human
Tissue:  Leukocytes and platelets.
References:  12
Regulation of angiogenesis and inflammatory response.
Species:  Mouse
Tissue:  In vivo
References:  16
Mediation of lipopolysaccharide (LPS)-induced systemic inflammation.
Species:  Rat
Tissue:  In vivo.
References:  27
Parasite phagocytosis.
Species:  Mouse
Tissue:  Cardiac tissue.
References:  56
Upregulation of bradykinin B1 receptors as measured by bradykinin-induced oedema.
Species:  Rat
Tissue:  In vivo.
References:  15
Intrathecal administration of PAF induces tactile allodynia (pain induced from normally non-painful stimuli) and thermal hyperalgesia at the level of the spinal cord.
Species:  Mouse
Tissue:  In vivo.
References:  36
Neovascularisation (thought to be linked to the PAF-induced upregulation of angiogenic factors VEGF and FGF-2 as found in HUVECs).
Species:  Mouse
Tissue:  Cornea.
References:  31
Bronchoconstiction via the production of thromboxane A2, LTC4, LTD4 and LTE4.
Species:  Mouse
Tissue:  Airway smooth muscle.
References:  37
Platelet aggregation.
There appears to be a synergistic interaction between 5-HT and PAF on platelet aggregation, TXA2 formation and ERK1/2 phosphorylation. It is thought to involve PLC/Ca2+, COX and MAPK pathways.
Species:  Human
Tissue:  Platelets.
References:  50
Physiological Consequences of Altering Gene Expression
PAF receptor knockout mice exhibit reduced anaphylactic symptoms, although normal neuronal development, reproduction and responses to bacterial endotoxin.
A possible use for PAF receptor antagonists could be to prevent anaphylactic responses without serious side-effects.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  23
PAF receptor knockout mice exhibit a decreased airway hyperresponsiveness to muscarinic cholinergic stimulation in an asthma model, although no difference to the eosinophilic inflammatory response when compared to the wild-type.
This suggests that PAF acts downstream of the airway inflammation in brionchial asthma.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  25
PAF receptor knockout mice and wild-type mice were innoculated intranasally with S. pneumoniae. The knockout mice had an increased resistance to pneumococcal pneumonia compared to the wild-type mice.
This study suggests that S. pneumoniae uses the PAF receptor to induce pneumonia.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  46
The embryos of PAF receptor knockout mice show an increase in the thickness of the external granular layer of the cerebellum.
In vitro studies using cerebellar granule neurons from PAF receptor knockout mice show reduced migration when compared to wild-type neurons.
However, PAF still had some effect on the migration of the wild-type neurons, suggesting an additional receptor-independent pathway for PAF.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  57
PAF receptor knockout mice are found to be protected from the spacial learning deficits, increased oxidative stress, inflammatory signalling and apoptosis that are associated with intermittent hypoxia (IH) during sleep.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  47
PAF receptor knockout mice exhibit reduced high frequency stimulation-induced LTP in hippocampal dentate gyrus cells compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  9
PAF receptor knockout mice and wild-type mice were infected with Strongyloides venezuelensis. The PAF receptor knockout mice exhibited a decrease in inflammatory response and subsequent delay in worm elimination. They also showed a reduction in the number of eggs produced by the worms, suggesting that PAF receptor-mediated responses may effect egg output.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  41
Transgenic mice overexpressing the PAF receptor exhibit enhanced acid aspiration-induced lung injury and respitatory failure.
PAF receptor knockout mice exhibit reduced acid aspiration-induced lung injury and respitatory failure.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  38
Transgenic mice overexpressing the PAF receptor exhibit epidermal hyperproliferation and an increase in dermal melanocytes. The PAF receptor gene was found in keratinocytes, not melanocytes, suggesting that the receptor has a role in the growth of epidermal keratinocytes.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  48
Comparison of PAF receptor knockout mice and wild-type mice following ovariectomies suggested that the PAF receptor links eostrogen depletion with osteoporosis.
It is suggested that a reduction in eostrogen enhances PAF production. In wild-type mice this alters osteoclast cell functions and leads to bone resorption. In PAF receptor knockout mice this bone loss is reduced.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  22
PAF receptor knockout mice exhibit increased angiogenesis and decreased inflammation in comparison to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  16
PAF receptor knockout mice infected with the hemoflagellate parasite Trypanosoma cruzi exhibited increased parasite replication and increased inflammatory response.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  56
Transgenic mice overexpressing the PAF receptor exhibited bronchoconstiction mediated via the PAF-induced production of thromboxane A2 and and cysteneinly leukotrienes LTC4, LTD4 and LTE4.
Species:  Mouse
Tissue: 
Technique:  Transgenesis.
References:  37
Transgenic mice overexpressing the PAF receptor exhibit hyperresponsiveness to metacholine and PAF, blocked by atropine. This suggests that this hyperresponsiveness may involve the muscarinic pathway.
Species:  Mouse
Tissue: 
Technique:  Transgenesis.
References:  39
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Ptafrtm1Eit Ptafrtm1Eit/Ptafrtm1Eit
involves: C57BL/6		 MGI:106066  MP:0005167 abnormal blood-brain barrier function PMID: 16299272 
Ptafrtm1Eit Ptafrtm1Eit/Ptafrtm1Eit
involves: C57BL/6		 MGI:106066  MP:0004003 abnormal vascular endothelial cell physiology PMID: 16299272 
Ptafrtm1Tksh Ptafrtm1Tksh/Ptafrtm1Tksh
involves: 129P2/OlaHsd * C57BL/6		 MGI:106066  MP:0001876 decreased inflammatory response PMID: 14742561 
Ptafrtm1Tksh Ptafrtm1Tksh/Ptafrtm1Tksh
C57BL/6-Ptafr		 MGI:106066  MP:0002411 decreased susceptibility to bacterial infection PMID: 14767826 
Ptafrtm1Tksh Ptafrtm1Tksh/Ptafrtm1Tksh
involves: 129P2/OlaHsd * C57BL/6		 MGI:106066  MP:0005027 increased susceptibility to parasitic infection PMID: 14742561 
Ptafrtm1Tksh Ptafrtm1Tksh/Ptafrtm1Tksh
involves: 129P2/OlaHsd * C57BL/6		 MGI:106066  MP:0005596 increased susceptibility to type I hypersensitivity reaction PMID: 9607919 
Biologically Significant Variants
An Ala224 -> Asp substitution in the 3rd cytoplasmic loop of the PAF receptor has been found in Japanese subjects, with an estimated allele frequency of 7.8% among the Japanese population.
This polymorphism has been linked to an increased susceptibility to multiple sclerosis.
Type:  Single nucleotide polymorphism.
Species:  Human
References:  18,42
General Comments
Transgenic mice overexpressing the guinea-pig PAF receptor have shown bronchial hyperreactivity to methacholine and increased mortality when exposed to bacterial endotoxin [26].

REFERENCES

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9. Chen, C., Magee, J. C., Marcheselli, V., Hardy, M. and Bazan, N. G. (2001) Attenuated LTP in hippocampal dentate gyrus neurons of mice deficient in the PAF receptor. J Neurophysiol, 85: 384-390. [PMID:11152738]

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13. Deo, D. D., Bazan, N. G. and Hunt, J. D. (2004) Activation of platelet-activating factor receptor-coupled G alpha q leads to stimulation of Src and focal adhesion kinase via two separate pathways in human umbilical vein endothelial cells. J Biol Chem, 279: 3497-3508. [PMID:14617636]

14. Desplat, V., Besse, A., Faucher, J. L., Praloran, V. and Denizot, Y. (1999) Expression of platelet-activating factor receptor transcript-1 but not transcript-2 by human bone marrow cells. Stem Cells, 17: 121-124. [PMID:10195573]

15. Fernandes, E. S., Passos, G. F., Campos, M. M., Araujo, J. G., Pesquero, J. L., Avelllar, M. C., Teixeira, M. M. and Calixto, J. B. (2003) Mechanisms underlying the modulatory action of platelet activating factor (PAF) on the upregulation of kinin B1 receptors in the rat paw. Br J Pharmacol, 139: 973-981. [PMID:12839871]

16. Ferreira, M. A., Barcelos, L. S., Campos, P. P., Vasconcelos, A. C., Teixeira, M. M. and Andrade, S. P. (2004) Sponge-induced angiogenesis and inflammation in PAF receptor-deficient mice (PAFR-KO). Br J Pharmacol, 141: 1185-1192. [PMID:15023865]

17. Flickinger, B. D. and Olson, M. S. (1999) Localization of the platelet-activating factor receptor to rat pancreatic microvascular endothelial cells. Am J Pathol, 154: 1353-1358. [PMID:10329588]

18. Fukunaga, K., Ishii, S., Asano, K., Yokomizo, T., Shiomi, T., Shimizu, T. and Yamaguchi, K. (2001) Single nucleotide polymorphism of human platelet-activating factor receptor impairs G-protein activation. J Biol Chem, 276: 43025-43030. [PMID:11560941]

19. Goldring, W. P., Alexander, S. P., Kendall, D. A. and Pattenden, G. (2005) Novel phomactin analogues as PAF receptor ligands. Bioorg Med Chem Lett, 15: 3263-3266. [PMID:15922596]

20. Handley, D. A., Van Valen, R. G., Melden, M. K., Houlihan, W. J. and Saunders, R. N. (1988) Biological effects of the orally active platelet activating factor receptor antagonist SDZ 64-412. J Pharmacol Exp Ther, 247: 617-623. [PMID:3183958]

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22. Hikiji, H., Ishii, S., Shindou, H., Takato, T. and Shimizu, T. (2004) Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy. J Clin Invest, 114: 85-93. [PMID:15232615]

23. Ishii, S., Kuwaki, T., Nagase, T., Maki, K., Tashiro, F., Sunaga, S., Cao, W. H., Kume, K., Fukuchi, Y., Ikuta, K., Miyazaki, J., Kumada, M. and Shimizu, T. (1998) Impaired anaphylactic responses with intact sensitivity to endotoxin in mice lacking a platelet-activating factor receptor. J Exp Med, 187: 1779-1788. [PMID:9607919]

24. Ishii, S., Matsuda, Y., Nakamura, M., Waga, I., Kume, K., Izumi, T. and Shimizu, T. (1996) A murine platelet-activating factor receptor gene: cloning, chromosomal localization and up-regulation of expression by lipopolysaccharide in peritoneal resident macrophages. Biochem J, 314: 671-678. [PMID:8670084]

25. Ishii, S., Nagase, T., Shindou, H., Takizawa, H., Ouchi, Y. and Shimizu, T. (2004) Platelet-activating factor receptor develops airway hyperresponsiveness independently of airway inflammation in a murine asthma model. J Immunol, 172: 7095-7102. [PMID:15153532]

26. Ishii, S., Nagase, T., Tashiro, F., Ikuta, K., Sato, S., Waga, I., Kume, K., Miyazaki, J. and Shimizu, T. (1997) Bronchial hyperreactivity, increased endotoxin lethality and melanocytic tumorigenesis in transgenic mice overexpressing platelet-activating factor receptor. Embo J, 16: 133-142. [PMID:9009274]

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To cite this database page, please use the following:

Rebecca Hills, Mark Whittaker.
Platelet-activating factor receptor: PAF receptor. Last modified on 15/02/2013. Accessed on 22/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=334.


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