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Review
. 2017 Oct;40(5):245-256.
doi: 10.1016/j.bj.2017.06.010. Epub 2017 Nov 10.

P2X4: A Fast and Sensitive Purinergic Receptor

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Free PMC article
Review

P2X4: A Fast and Sensitive Purinergic Receptor

Jaanus Suurväli et al. Biomed J. .
Free PMC article

Abstract

Extracellular nucleotides have been recognized as important mediators of activation, triggering multiple responses via plasma membrane receptors known as P2 receptors. P2 receptors comprise P2X ionotropic receptors and G protein-coupled P2Y receptors. P2X receptors are expressed in many tissues, where they are involved in a number of functions including synaptic transmission, muscle contraction, platelet aggregation, inflammation, macrophage activation, differentiation and proliferation, neuropathic and inflammatory pain. P2X4 is one of the most sensitive purinergic receptors (at nanomolar ATP concentrations), about one thousand times more than the archetypal P2X7. P2X4 is widely expressed in central and peripheral neurons, in microglia, and also found in various epithelial tissues and endothelial cells. It localizes on the plasma membrane, but also in intracellular compartments. P2X4 is preferentially localized in lysosomes, where it is protected from proteolysis by its glycosylation. High ATP concentration in the lysosomes does not activate P2X4 at low pH; P2X4 gets activated by intra-lysosomal ATP only in its fully dissociated tetra-anionic form, when the pH increases to 7.4. Thus, P2X4 is functioning as a Ca2+-channel after the fusion of late endosomes and lysosomes. P2X4 modulates major neurotransmitter systems and regulates alcohol-induced responses in microglia. P2X4 is one of the key receptors mediating neuropathic pain. However, injury-induced upregulation of P2X4 expression is gender dependent and plays a key role in pain difference between males and females. P2X4 is also involved in inflammation. Extracellular ATP being a pro-inflammatory molecule, P2X4 can trigger inflammation in response to high ATP release. It is therefore involved in multiple pathologies, like post-ischemic inflammation, rheumatoid arthritis, airways inflammation in asthma, neurodegenerative diseases and even metabolic syndrome. Although P2X4 remains poorly characterized, more studies are needed as it is likely to be a potential therapeutic target in these multiple pathologies.

Keywords: ATP; Neuropathic pain; P2X receptor; P2X4; Purinergic signaling.

Figures

Fig. 1
Fig. 1
P2X4 sequences from multiple vertebrates. (A) Multiple alignment of P2X4 from different vertebrate species. Positions of the cysteines are highlighted in yellow, and conserved residues involved in ATP binding are on green background. The two trans-membrane regions are underlined, the extracellular (or “out” part of the protein is located between them. Interestingly, the C-terminus region, which in P2X7 contains the palmitoylated cysteines (represented in red on yellow background), is not conserved in P2X4 sequences. (B) NJ distance tree of P2X4 sequences. In zebrafish, P2X4b is located on Chr 8 close to P2X7, while P2X4a is on Chr21; the genomic contexts on these paralogs are different and do not allow to reconstitute a simple duplication history. Accession numbers: Human P2RX4: ENSP00000336607; Mouse P2RX4:: ENSMUSP00000031429; Chicken P2RX4: ENSGALP00000006190; Zebrafish P2RX4A: ENSDARP00000108004; Zebrafish P2RX4b: ENSDARP00000089740; Human P2RX7: ENSP00000330696).
Fig. 2
Fig. 2
P2X4 intracellular distribution. P2X4 is located mainly in lysosomes and is involved in the fusion of late endosomes with lysosomes as a Ca2+-channel. Arrows represent transfer of P2X4 between different compartments. P2X4 is represented in open or closed configuration, depending on the availability of ATP4− (represented as a blue star).
Fig. 3
Fig. 3
P2X4 regulation pathways. Binding of ATP activates P2X4R and initiates signalling: agonist binding is closing the cleft in the intersubunit binding site – that is opening the ion channel. The open state of P2x4R is accessible for binding of allosteric modulators for example ivermectin. Note that α,β-methylene ATP (α,β-MeATP) is a partial agonist when compared to ATP because the currents triggered by α,β-MeATP are lower that those elicited by ATP. P2X4 is in an open conformation when bound to ATP in reconstituted high-density lipoproteins as shown in zebrafish . In contrast, when P2X4 was bound to α,β-MeATP, the transmembrane domain and the lower body of P2X4 are in equilibrium between closed and open conformations. The small proportion of P2X4 in the open conformation may thus spark partial activation of the receptors. 5-BDBD: 5-(3-Bromophenyl)-1,3-dihydro-2H-Benzofuro[3,2-e]-1,4-diazepin-2-one; TNP–ATP: 2′,3′-O-(2,4,6-trinitrophenyl)adenosine 5′-triphosphate – antagonist of P2X1-4R; PPADs: pyridoxalphosphate-6-azophenyl-2′,4′-disulphonoic acid = an antagonist of P2X1-3,5,7R but not P2X4R; NP-1815-PX: (5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione); BzATP: 2′,3′-O-(4-benzoyl-benzoyl)-ATP.

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