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P2X purinoreceptor

(Redirected fromP2X Receptors)
"P2X" redirects here. Not to be confused withPower-to-X.

TheP2X receptors,alsoATP-gated P2X receptor cation channel family,[1]is aprotein familythat consists of cation-permeableligand-gated ion channelsthat open in response to the binding of extracellularadenosine 5'-triphosphate(ATP). They belong to a larger family of receptors known as the ENaC/P2X superfamily.[1]ENaC and P2X receptors have similar 3-D structures and are homologous.[2]P2X receptors are present in a diverse array of organisms includinghumans,mouse,rat,rabbit,chicken,zebrafish,bullfrog,fluke,andamoeba.[3]

ATP P2X receptor
Figure 1. Schematic representation showing the membrane topology of a typical P2X receptor subunit. First and second transmembrane domains are labeled TM1 and TM2.
Identifiers
SymbolP2X_receptor
PfamPF00864
InterProIPR001429
PROSITEPDOC00932
TCDB1.A.7
OPM superfamily181
OPM protein3h9v
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary
Figure 2. Crystal structure of the zebrafish P2X4receptor (deltaP2X4-B) channel as viewed from the side (left), extracellular (top right), and intracellular (bottom right) perspectives(PDB:3I5D​)

Physiological roles

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P2X receptors are involved in a variety of physiological processes,[3][4]including:

Tissue distribution

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P2X receptors are expressed in cells from a wide variety of animaltissues.On presynaptic and postsynapticnerve terminalsandglialcells throughout thecentral,peripheralandautonomicnervous systems, P2X receptors have been shown to modulatesynaptic transmission.[3][12]Furthermore, P2X receptors are able to initiatecontractionin cells of theheart muscle,skeletal muscle,and varioussmooth muscletissues, including that of thevasculature,vas deferensandurinary bladder.P2X receptors are also expressed onleukocytes,including lymphocytes and macrophages, and are present on bloodplatelets.There is some degree of subtype specificity as to which P2X receptor subtypes are expressed on specific cell types, with P2X1receptors being particularly prominent in smooth muscle cells, and P2X2being widespread throughout the autonomic nervous system. However, such trends are very general and there is considerable overlap in subunit distribution, with most cell types expressing more than one subunits. For example, P2X2and P2X3subunits are commonly found co-expressed insensory neurons,where they often co-assemble into functional P2X2/3receptors.

Basic structure and nomenclature

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To date, seven separate genes coding for P2X subunits have been identified, and named asP2X1throughP2X7,based on their pharmacological properties.[3][13]

receptor subtype HGNCgene name chromosomal location
P2X1 P2RX1 17p13.3
P2X2 P2RX2 12q24.33
P2X3 P2RX3 11q12
P2X4 P2RX4 12q24.32
P2X5 P2RX5 17p13.3
P2X6 P2RX6 22p11.21
P2X7 P2RX7 12q24.31

The proteins of the P2X receptors are quite similar in sequence (>35% identity), but they possess 380-1000 amino acyl residues per subunit with variability in length. The subunits all share a common topology, possessing twotransmembrane domains(one about 30-50 residues from their N-termini, the other near residues 320-340), a large extracellular loop and intracellularcarboxylandaminotermini (Figure 1)[3]The extracellular receptor domains between these two segments (of about 270 residues) are well conserved with several conserved glycyl residues and 10 conserved cysteyl residues. The amino termini contain a consensus site forprotein kinase Cphosphorylation, indicating that the phosphorylation state of P2X subunits may be involved in receptor functioning.[14]Additionally, there is a great deal of variability (25 to 240 residues) in the C termini, indicating that they might serve subunit specific properties.[15]

Generally speaking, most subunits can form functionalhomomericorheteromericreceptors.[16]Receptor nomenclature dictates that naming is determined by the constituent subunits; e.g. a homomeric P2X receptor made up of only P2X1subunits is called a P2X1receptor, and a heteromeric receptor containing P2X2and P2X3subunits is called a P2X2/3receptor. The general consensus is that P2X6cannot form a functional homomeric receptor and that P2X7cannot form a functional heteromeric receptor.[17][18]

Topologically, they resemble theepithelial Na+channel proteinsin possessing (a) N- and C-termini localized intracellularly, (b) two putative transmembrane segments, (c) a large extracellular loop domain, and (d) many conserved extracellular cysteyl residues. P2X receptor channels transport small monovalent cations, although some also transport Ca2+.[19]

Evidence from early molecular biological and functional studies has strongly indicated that the functional P2X receptor protein is atrimer,with the three peptidesubunitsarranged around an ion-permeable channel pore.[20]This view was recently confirmed by the use ofX-ray crystallographyto resolve thethree-dimensional structureof thezebrafishP2X4receptor[21](Figure 2). These findings indicate that the second transmembrane domain of each subunit lines the ion-conducting pore and is therefore responsible for channelgating.[22]

The relationship between the structure and function of P2X receptors has been the subject of considerable research usingsite-directed mutagenesisandchimeric channels,and key protein domains responsible for regulating ATP binding, ion permeation, pore dilation and desensitization have been identified.[23][24]

Activation and channel opening

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Three ATP molecules are thought to be required to activate a P2X receptor, suggesting that ATP needs to bind to each of the three subunits in order to open the channel pore, though recent evidence suggests that ATP binds at the three subunit interfaces.[25][26]Once ATP binds to the extracellular loop of the P2X receptor, it evokes aconformational changein the structure of the ion channel that results in the opening of the ion-permeable pore. The most commonly accepted theory of channel opening involves the rotation and separation of the second transmembrane domain (TM) helices, allowing cations such asNa+andCa2+to access the ion-conducting pore through three lateralfenestrationsabove the TM domains.[27][28]The entry of cations leads to thedepolarizationof the cell membrane and the activation of various Ca2+-sensitive intracellular processes.[29][30]The channel opening time is dependent upon the subunit makeup of the receptor. For example, P2X1and P2X3receptorsdesensitizerapidly (a few hundred milliseconds) in the continued presence of ATP, whereas the P2X2receptor channel remains open for as long as ATP is bound to it.

Transport reaction

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The generalized transport reaction is:

Monovalent cations or Ca2+(out) ⇌ monovalent cations or Ca2+(in)

Pharmacology

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The pharmacology of a given P2X receptor is largely determined by its subunit makeup.[13]Different subunits exhibit different sensitivities to purinergic agonists such as ATP, α,β-meATP and BzATP; and antagonists such aspyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid(PPADS) andsuramin.[3]Of continuing interest is the fact that some P2X receptors (P2X2,P2X4,human P2X5,and P2X7) exhibit multiple open states in response to ATP, characterized by a time-dependent increase in the permeabilities of large organic ions such asN-methyl-D-glucamine(NMDG+) and nucleotide binding dyes such aspropidium iodide(YO-PRO-1). Whether this change in permeability is due to a widening of the P2X receptor channel pore itself or the opening of a separate ion-permeable pore is the subject of continued investigation.[3]

Synthesis and trafficking

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P2X receptors are synthesized in the roughendoplasmic reticulum.After complex glycosylation in theGolgi apparatus,they are transported to the plasma membrane, whereby docking is achieved through specific members of theSNARE proteinfamily.[16]A YXXXKmotifin the C terminus is common to all P2X subunits and seems to be important fortraffickingand stabilization of P2X receptors in the membrane.[31]Removal of P2X receptors occurs viaclathrin-mediatedendocytosisof receptors toendosomeswhere they are sorted intovesiclesfor degradation or recycling.[32]

Allosteric modulation

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The sensitivity of P2X receptors to ATP is strongly modulated by changes in extracellular pH and by the presence of heavy metals (e.g. zinc and cadmium). For example, the ATP sensitivity of P2X1,P2X3and P2X4receptors is attenuated when the extracellular pH<7, whereas the ATP sensitivity of P2X2is significantly increased. On the other hand, zinc potentiates ATP-gated currents through P2X2,P2X3and P2X4,and inhibits currents through P2X1.Theallosteric modulationof P2X receptors by pH and metals appears to be conferred by the presence of histidine side chains in the extracellular domain.[3]In contrast to the other members of the P2X receptor family, P2X4receptors are also very sensitive to modulation by the macrocyclic lactone,ivermectin.[33]Ivermectin potentiates ATP-gated currents through P2X4receptors by increasing the open probability of the channel in the presence of ATP, which it appears to do by interacting with the transmembrane domains from within the lipid bilayer.[34]

Subfamilies

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Human proteins containing this domain

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P2RX1;P2RX2;P2RX3;P2RX4;P2RX5;P2RX7;P2RXL1;TAX1BP3

See also

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References

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  1. ^ab"ATP-gated P2X Receptor Cation Channel (P2X Receptor) Family".Functional and Phylogenetic Classification of Membrane Transport Proteins.Saier Lab. Group, UCSD and SDSC.
  2. ^Chen JS, Reddy V, Chen JH, Shlykov MA, Zheng WH, Cho J, Yen MR, Saier MH (2011)."Phylogenetic characterization of transport protein superfamilies: superiority of SuperfamilyTree programs over those based on multiple alignments".J. Mol. Microbiol. Biotechnol.21(3–4): 83–96.doi:10.1159/000334611.PMC3290041.PMID22286036.
  3. ^abcdefghijNorth RA (2002). "Molecular physiology of P2X receptors".Physiological Reviews.82(4): 1013–1067.doi:10.1152/physrev.00015.2002.PMID12270951.
  4. ^Khakh BS, North RA (2006). "P2X receptors as cell-surface ATP sensors in health and disease".Nature.442(7102): 527–32.Bibcode:2006Natur.442..527K.doi:10.1038/nature04886.PMID16885977.S2CID4422150.
  5. ^Vassort G (2001). "Adenosine 5'-triphosphate: a P2-purinergic agonist in the myocardium".Physiol. Rev.81(2): 767–806.doi:10.1152/physrev.2001.81.2.767.PMID11274344.
  6. ^Chizh BA, Illes P (2001)."P2X receptors and nociception".Pharmacol. Rev.53(4): 553–68.PMID11734618.
  7. ^Fowler CJ, Griffiths D, de Groat WC (2008)."The neural control of micturition".Nat Rev Neurosci.9(6): 453–466.doi:10.1038/nrn2401.PMC2897743.PMID18490916.
  8. ^Gachet C (2006). "Regulation of Platelet Functions by P2 Receptors".Annual Review of Pharmacology and Toxicology.46:277–300.doi:10.1146/annurev.pharmtox.46.120604.141207.PMID16402906.
  9. ^Wewers MD, Sarkar A (2009)."P2X7 receptor and macrophage function".Purinergic Signalling.5(2): 189–195.doi:10.1007/s11302-009-9131-9.PMC2686821.PMID19214778.
  10. ^Kawano A, Tsukimoto M, Noguchi T, Hotta N, Harada H, Takenouchi T, Kitani H, Kojima S (2012). "Involvement of P2X4 receptor in P2X7 receptor-dependent cell death of mouse macrophages".Biochemical and Biophysical Research Communications.419(2): 374–380.doi:10.1016/j.bbrc.2012.01.156.PMID22349510.
  11. ^Burnstock G (2013). "Introduction to Purinergic Signalling in the Brain".Glioma Signaling.Advances in Experimental Medicine and Biology. Vol. 986. pp. 1–12.doi:10.1007/978-94-007-4719-7_1.ISBN978-94-007-4718-0.PMID22879061.
  12. ^Burnstock G (2000)."P2X receptors in sensory neurones".Br J Anaesth.84(4): 476–88.doi:10.1093/oxfordjournals.bja.a013473.PMID10823099.
  13. ^abGever JR, Cockayne DA, Dillon MP, Burnstock G, Ford AP (2006). "Pharmacology of P2X channels".Pflügers Arch.452(5): 513–37.doi:10.1007/s00424-006-0070-9.PMID16649055.S2CID15837425.
  14. ^Boué-Grabot E, Archambault V, Séguéla P (2000)."A protein kinase C site highly conserved in P2X subunits controls the desensitization kinetics of P2X(2) ATP-gated channels".The Journal of Biological Chemistry.275(14): 10190–10195.doi:10.1074/jbc.275.14.10190.PMID10744703.
  15. ^Surprenant A, North RA (2009). "Signaling at Purinergic P2X Receptors".Annual Review of Physiology.71:333–359.doi:10.1146/annurev.physiol.70.113006.100630.PMID18851707.
  16. ^abKaczmarek-Hájek K, Lörinczi E, Hausmann R, Nicke A (2012)."Molecular and functional properties of P2X receptors—recent progress and persisting challenges".Purinergic Signalling.8(3): 375–417.doi:10.1007/s11302-012-9314-7.PMC3360091.PMID22547202.
  17. ^Barrera NP, Ormond SJ, Henderson RM, Murrell-Lagnado RD, Edwardson JM (2005)."Atomic Force Microscopy Imaging Demonstrates that P2X2 Receptors Are Trimers but That P2X6 Receptor Subunits Do Not Oligomerize".Journal of Biological Chemistry.280(11): 10759–10765.doi:10.1074/jbc.M412265200.PMID15657042.
  18. ^Torres GE, Egan TM, Voigt MM (1999)."Hetero-oligomeric assembly of P2X receptor subunits. Specificities exist with regard to possible partners".The Journal of Biological Chemistry.274(10): 6653–6659.doi:10.1074/jbc.274.10.6653.PMID10037762.
  19. ^US Lapsed 6498022,Yale University School Of Medicine, "Isolated nucleic acid molecules encoding human carbonate transporter proteins, and uses thereof", assigned to Applera Corporation, ConnecticutThis article incorporates text from this source, which is in thepublic domain.
  20. ^Nicke A, Bäumert HG, Rettinger J, Eichele A, Lambrecht G, Mutschler E, Schmalzing G (1998)."P2X1 and P2X3 receptors form stable trimers: a novel structural motif of ligand-gated ion channels".EMBO J.17(11): 3016–28.doi:10.1093/emboj/17.11.3016.PMC1170641.PMID9606184.
  21. ^Kawate T, Michel JC, Birdsong WT, Gouaux E (2009)."Crystal structure of the ATP-gated P2X4 ion channel in the closed state".Nature.460(7255): 592–598.Bibcode:2009Natur.460..592K.doi:10.1038/nature08198.PMC2720809.PMID19641588.
  22. ^Migita K, Haines WR, Voigt MM, Egan TM (2001)."Polar Residues of the Second Transmembrane Domain Influence Cation Permeability of the ATP-gated P2X2 Receptor".Journal of Biological Chemistry.276(33): 30934–30941.doi:10.1074/jbc.M103366200.PMID11402044.
  23. ^Egan TM, Samways DS, Li Z (2006). "Biophysics of P2X receptors".Pflügers Arch.452(5): 501–12.doi:10.1007/s00424-006-0078-1.PMID16708237.S2CID20394414.
  24. ^Roberts JA, Vial C, Digby HR, Agboh KC, Wen H, Atterbury-Thomas A, Evans RJ (2006). "Molecular properties of P2X receptors".Pflügers Arch.452(5): 486–500.doi:10.1007/s00424-006-0073-6.PMID16607539.S2CID15079763.
  25. ^Evans RJ (2008)."Orthosteric and allosteric binding sites of P2X receptors".Eur. Biophys. J.38(3): 319–27.doi:10.1007/s00249-008-0275-2.PMID18247022.
  26. ^Ding S, Sachs F (1999)."Single channel properties of P2X2 purinoceptors".The Journal of General Physiology.113(5): 695–720.doi:10.1085/jgp.113.5.695.PMC2222910.PMID10228183.
  27. ^Cao L, Broomhead HE, Young MT, North RA (2009)."Polar Residues in the Second Transmembrane Domain of the Rat P2X2 Receptor That Affect Spontaneous Gating, Unitary Conductance, and Rectification".Journal of Neuroscience.29(45): 14257–14264.doi:10.1523/JNEUROSCI.4403-09.2009.PMC2804292.PMID19906973.
  28. ^Kawate T, Robertson JL, Li M, Silberberg SD, Swartz KJ (2011)."Ion access pathway to the transmembrane pore in P2X receptor channels".The Journal of General Physiology.137(6): 579–590.doi:10.1085/jgp.201010593.PMC3105519.PMID21624948.
  29. ^Shigetomi E, Kato F (2004)."Action Potential-Independent Release of Glutamate by Ca2+ Entry through Presynaptic P2X Receptors Elicits Postsynaptic Firing in the Brainstem Autonomic Network".Journal of Neuroscience.24(12): 3125–3135.doi:10.1523/JNEUROSCI.0090-04.2004.PMC6729830.PMID15044552.
  30. ^Koshimizu TA, Van Goor F, Tomić M, Wong AO, Tanoue A, Tsujimoto G, Stojilkovic SS (2000). "Characterization of calcium signaling by purinergic receptor-channels expressed in excitable cells".Molecular Pharmacology.58(5): 936–945.doi:10.1124/mol.58.5.936.PMID11040040.
  31. ^Chaumont S, Jiang LH, Penna A, North RA, Rassendren F (2004)."Identification of a Trafficking Motif Involved in the Stabilization and Polarization of P2X Receptors".Journal of Biological Chemistry.279(28): 29628–29638.doi:10.1074/jbc.M403940200.PMID15126501.
  32. ^Royle SJ, Bobanović LK, Murrell-Lagnado RD (2002)."Identification of a Non-canonical Tyrosine-based Endocytic Motif in an Ionotropic Receptor".Journal of Biological Chemistry.277(38): 35378–35385.doi:10.1074/jbc.M204844200.PMID12105201.
  33. ^Khakh BS, Proctor WR, Dunwiddie TV, Labarca C, Lester HA (1999)."Allosteric control of gating and kinetics at P2X(4) receptor channels".J. Neurosci.19(17): 7289–99.doi:10.1523/JNEUROSCI.19-17-07289.1999.PMC6782529.PMID10460235.
  34. ^Priel A, Silberberg SD (2004)."Mechanism of ivermectin facilitation of human P2X4receptor channels ".J. Gen. Physiol.123(3): 281–93.doi:10.1085/jgp.200308986.PMC2217454.PMID14769846.
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