P2RX4

P2RX4
Identifiers
Aliases	P2RX4, P2X4, P2X4R, purinergic receptor P2X 4
External IDs	MGI: 1338859 HomoloGene: 1923 GeneCards: P2RX4
Targeted by Drug
adenosine triphosphate[1]
Gene ontology Molecular function • protein homodimerization activity • zinc ion binding • cadherin binding • purinergic nucleotide receptor activity • extracellular ATP-gated cation channel activity • ion channel activity • protein binding • drug binding • copper ion binding • receptor binding • ATP binding Cellular component • integral component of membrane • membrane • postsynaptic density • dendritic spine • integral component of nuclear inner membrane • synapse • integral component of plasma membrane • lysosomal membrane • cell junction • neuronal cell body • terminal bouton • axon • dendrite • perinuclear region of cytoplasm • extracellular exosome • plasma membrane Biological process • response to ATP • positive regulation of calcium-mediated signaling • positive regulation of calcium ion transport into cytosol • negative regulation of cardiac muscle hypertrophy • regulation of sodium ion transport • positive regulation of nitric oxide biosynthetic process • membrane depolarization • endothelial cell activation • ion transport • cation transmembrane transport • response to fluid shear stress • regulation of blood pressure • ion transmembrane transport • positive regulation of prostaglandin secretion • tissue homeostasis • transport • apoptotic signaling pathway • sensory perception of pain • regulation of cardiac muscle contraction • cellular response to ATP • protein homooligomerization • relaxation of cardiac muscle • signal transduction • neuronal action potential • purinergic nucleotide receptor signaling pathway • positive regulation of calcium ion transport • blood coagulation Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5025	18438
Ensembl	ENSG00000135124	ENSMUSG00000029470
UniProt	Q99571	Q9JJX6
RefSeq (mRNA)	NM_001256796 NM_001261397 NM_001261398 NM_002560 NM_175567 NM_175568	NM_011026 NM_001310718 NM_001310720
RefSeq (protein)	NP_001243725.1 NP_001248326.1 NP_002551.2	n/a
Location (UCSC)	Chr 12: 121.21 – 121.23 Mb	Chr 5: 122.71 – 122.73 Mb
PubMed search	[2]	[3]
Wikidata

P2X purinoceptor 4 is a protein that in humans is encoded by the P2RX4 gene.^[4][5] The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced transcript variants have been identified for this gene although their full-length natures have not been determined.^[5]

The receptor is found in the central and peripheral nervous systems, in the epithelia of ducted glands and airways, in the smooth muscle of the bladder, gastrointestinal tract, uterus, and arteries, in uterine endometrium, and in fat cells.^[6] P2X₄ receptors have been implicated in the regulation of cardiac function, ATP-mediated cell death, synaptic strengthening, and activating of the inflammasome in response to injury.^{[7][8][9][10][11]}

Receptor Structure and Kinetics

The P2X₄ subunits can form homomeric or heteromeric receptors.^[12] The P2X₄ receptor has a typical P2X receptor structure. The zebrafish P2X₄ receptor was the first purinergic receptor to be crystallized and have its three-dimensional structure solved, forming the model for the P2X receptor family.^[13] The P2X₄ receptor is a ligand-gated cation channel that opens in response to ATP binding.^[14] The P2X₄ receptor has high calcium permeability, leading to the depolarization of the cell membrane and the activation of various Ca²⁺-sensitive intracellular processes.^[14][15][16] Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG⁺) in about 50% of the cells expressing the P2X₄ receptor.^[14] The desensitization of P2X₄ receptors is intermediate when compared to P2X1 and P2X2 receptors.^[14]

Pharmacology

Agonists

P2X₄ receptors respond to ATP, but not αβmeATP. These receptors are also potentiated by ivermectin, cibacron blue, and zinc.^[14]

Antagonists

The main pharmacological distinction between the members of the purinoceptor family is the relative sensitivity to the antagonists suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). The product of this gene has the lowest sensitivity for these antagonists^[14]

Receptor Trafficking

P2X₄ receptors are stored in lysosomes and brought to the cell surface in response to extracellular signals.^[17] These signals include IFN-γ, CCL21, CCL2.^[18][19][20] Fibronectin is also involved in upregulation of P2X₄ receptors through interactions with integrins that lead to the activation of SRC-family kinase member, Lyn.^[21] Lyn then activates PI3K-AKT and MEK-ERK signaling pathways to stimulate receptor trafficking.^[22] Internalization of P2X₄ receptors is clathrin- and dynamin-dependent endocytosis.^[23]

Neuropathic Pain

The P2X₄ receptor has been linked to neuropathic pain mediated by microglia in vitro and in vivo.^[24][25] P2X₄ receptors are upregulated following injury.^[26] This upregulation allows for increased activation of p38 mitogen-activated protein kinases, thereby increasing the release of brain-derived neurotrophic factor (BDNF) from microglia.^[27] BDNF released from microglia induces neuronal hyperexcitability through interaction with the TrkB receptor.^[28] More importantly, recent work shows that P2X₄ receptor activation is not only necessary for neuropathic pain, but it is also sufficient to cause neuropathic pain.^[29]

See also

• P2X receptor

References

Further reading

External links

• P2RX4 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.