{"history":[],"article":{"id":"3edb1841-c948-4ebc-a2b9-4e13e4cca1ec","title":"P2RX4","slug":"p2rx4","content":":::summary\n:::\n\n# \n**P2X purinoceptor 4** is a [protein](https://bliptext.com/articles/protein) that in humans is encoded by the P2RX4 [gene](https://bliptext.com/articles/gene).\nP2X purinoceptor 4 is a member of the [P2X receptor](https://bliptext.com/articles/p2x-purinoreceptor) family.\nP2X receptors are [trimeric](https://bliptext.com/articles/protein-trimer) protein complexes that can be [homomeric](https://bliptext.com/articles/homomeric) or [heteromeric](https://bliptext.com/articles/heteromer).\nThese receptors are [ligand-gated cation channels](https://bliptext.com/articles/ligand-gated-ion-channel) that open in response to ATP binding.\nEach receptor subtype, determined by the subunit composition, varies in its affinity to ATP and [desensitization kinetics](https://bliptext.com/articles/receptor-ligand-kinetics).\nThe **P2X4 receptor** is the [homotrimer](https://bliptext.com/articles/homotrimer) composed of three P2X4 monomers.\nThey are nonselective cation channels with high [calcium](https://bliptext.com/articles/calcium) permeability, leading to the [depolarization](https://bliptext.com/articles/depolarization) of the cell membrane and the activation of various Ca2+-sensitive intracellular processes.\nThe P2X4 receptor is uniquely expressed on [lysosomal compartments](https://bliptext.com/articles/lysosome) as well as the [cell surface](https://bliptext.com/articles/cell-membrane).\nThe 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](https://bliptext.com/articles/bladder), [gastrointestinal tract](https://bliptext.com/articles/gastrointestinal-tract), [uterus](https://bliptext.com/articles/uterus), and [arteries](https://bliptext.com/articles/artery), in uterine [endometrium](https://bliptext.com/articles/endometrium), and in [fat cells](https://bliptext.com/articles/adipocyte).\nP2X₄ receptors have been implicated in the regulation of cardiac function, ATP-mediated [cell death](https://bliptext.com/articles/apoptosis), [synaptic strengthening](https://bliptext.com/articles/long-term-potentiation), and activating of the [inflammasome](https://bliptext.com/articles/inflammasome) in response to injury.\n\n# Structure\nP2X receptors are composed of three subunits that can be homomeric or heteromeric by nature.\nIn mammals, there are seven different subunits, each encoded in a different gene (P2RX1-P2RX7).\nEach subunit has two [transmembrane](https://bliptext.com/articles/transmembrane-domain) [alpha helices](https://bliptext.com/articles/alpha-helix) (TM1 and TM2) linked by a large extracellular loop.\nAnalysis of [x-ray crystallographic](https://bliptext.com/articles/x-ray-crystallography) structures revealed a 'dolphin-like' [tertiary structure](https://bliptext.com/articles/protein-tertiary-structure), where the 'tail' is embedded in the [phospholipid bilayer](https://bliptext.com/articles/lipid-bilayer) and the upper and lower [ectodomains](https://bliptext.com/articles/ectodomain) form the 'head' and 'body' respectively.\nAdjacent interfaces of the subunits form a deep binding pocket for ATP.\nATP binding to these [orthosteric](https://bliptext.com/articles/allosteric-regulation) sites causes a shift in [conformation](https://bliptext.com/articles/conformational-change) opening the channel pore.\nThe P2X₄ subunits can form homomeric or heteromeric receptors.\nIn 2009, the first purinergic receptor crystallized was the closed state homomeric [zebrafish](https://bliptext.com/articles/zebrafish) P2X₄ receptor.\nAlthough truncated at its [N-](https://bliptext.com/articles/n-terminus) and [C- termini](https://bliptext.com/articles/c-terminus), this [crystal structure](https://bliptext.com/articles/crystal-structure) resolved and confirmed that these proteins were indeed [trimers](https://bliptext.com/articles/trimer-chemistry) with an ectodomain rich with [disulfide bonds](https://bliptext.com/articles/disulfide).\n# [Ribbon structures of (A) the P2X4 homotrimeric receptor and (B) the subunit monomer | upload.wikimedia.org/wikipedia/commons/4/4c/P2X4///receptor///open///state///and///monomer.jpg]\n\n# Gating mechanism\nP2X receptors have three confirmed conformational states: ATP-unbound closed, ATP-bound open, and ATP-bound desensitized.\nImaging of the human P2X3 and rat P2X7 receptors has revealed structural similarities and differences in their cytoplasmic domains.\nIn the ATP-bound state, both receptor types form [beta sheet](https://bliptext.com/articles/beta-sheet) structures from N- and C- termini of adjacent subunits.\nThese newly folded [secondary structures](https://bliptext.com/articles/protein-secondary-structure) come together to form a 'cytoplasmic cap' that helps stabilize the open pore.\nCrystal structures of the desensitized receptor no longer exhibit the cytoplasmic cap.\n# [Schematic of the P2X4 receptor conformational states | upload.wikimedia.org/wikipedia/commons/d/de/P2X4///hypothetical///gating///cycle.jpg]\n\n## Desensitization\n[Electrophysiology](https://bliptext.com/articles/electrophysiology) studies have revealed differences in the rates of receptor desensitization between different P2X subtypes.\n[Homotrimers](https://bliptext.com/articles/homotrimer) P2X1 and P2X3 are the fastest, with desensitization observed milliseconds after activation, while P2X2 and P2X4 receptors are on the timescale of seconds.\nNotably, the P2X7 receptor uniquely does not undergo desensitization.\nMutational studies working with the rat P2X2 and P2X3 receptors have identified three [residues](https://bliptext.com/articles/residue-biochemistry) in the N-terminus that majorly contribute to these differences.\nBy changing the [amino acids](https://bliptext.com/articles/amino-acid) in the P2X3 to match the analogous P2X2, the desensitization rate slowed down.\nConversely, changing residues of P2X2 to match P2X3 increased the desensitization rate.\nIn combination with the open state crystal structures, it was hypothesized that the cytoplasmic cap was stabilizing the open pore conformation.\nAdditionally, structural analysis of the open P2X3 receptor revealed transient changes in TM2, the transmembrane alpha helix lining the pore.\nWhile in the open state conformation, a small mid-region of TM2 develops into a [310-helix](https://bliptext.com/articles/310-helix).\nThis helical structure disappears with desensitization and instead TM2 reforms as a complete alpha helix repositioned closer to the extracellular side.\nThe helical recoil model uses the observed structural changes in TM2 and the transient formation of the cytoplasmic cap to describe a possible mechanism for the desensitization of P2X receptors.\nIn this model, it is theorized that the cytoplasmic cap fixes the intracellular end of the TM2 helix while stretching its extracellular end to allow ion influx.\nThis would induce the observed 310-helix.\nThe cap then disassembles and releases its hold on TM2 causing the helix to recoil towards the outer leaflet of the membrane.\nIn support of this theory, the P2X7 uniquely has a large cytoplasmic domain with [palmitoylated](https://bliptext.com/articles/palmitoylation) [C-cysteine anchor](https://bliptext.com/articles/lipid-anchored-protein) sites.\nThese sites further stabilize its cytoplasmic cap by anchoring the domain into the surrounding inner leaflet.\nMutations of the associated palmitoylation site residues cause observed atypical desensitization of the receptor.\n\n# Receptor trafficking\nP2X4 receptors are functionally expressed on both the cell surface and in lysosomes.\nAlthough preferentially localized and stored in [lysosomes](https://bliptext.com/articles/lysosome), P2X4 receptors are brought to the cell surface in response to extracellular signals.\nThese signals include [IFN-γ](https://bliptext.com/articles/interferon-gamma), [CCL21](https://bliptext.com/articles/ccl21), [CCL2](https://bliptext.com/articles/ccl2).\n[Fibronectin](https://bliptext.com/articles/fibronectin) is also involved in upregulation of P2X₄ receptors through interactions with [integrins](https://bliptext.com/articles/integrin) that lead to the activation of [SRC-family kinase](https://bliptext.com/articles/src-gene) member, [Lyn](https://bliptext.com/articles/lyn).\nLyn then activates [PI3K-AKT](https://bliptext.com/articles/pi3k-akt-mtor-pathway) and [MEK-ERK](https://bliptext.com/articles/mapk-erk) signaling pathways to stimulate receptor trafficking.\nInternalization of P2X₄ receptors is [clathrin](https://bliptext.com/articles/clathrin)- and [dynamin](https://bliptext.com/articles/dynamin)-dependent [endocytosis](https://bliptext.com/articles/endocytosis).\n\n# Pharmacology\n\n## Agonists\nP2X₄ receptors respond to ATP, but not αβmeATP.\nThese receptors are also potentiated by [ivermectin](https://bliptext.com/articles/ivermectin), cibacron blue, and [zinc](https://bliptext.com/articles/zinc).\n\n## Antagonists\nThe main pharmacological distinction between the members of the [purinoceptor](https://bliptext.com/articles/purinergic-receptor) family is the relative sensitivity to the antagonists [suramin](https://bliptext.com/articles/suramin) and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid ([PPADS](https://bliptext.com/articles/ppads)).\nThe product of this gene has the lowest sensitivity for these antagonists\n\n# Neuropathic pain\nThe P2X₄ receptor has been linked to [neuropathic pain](https://bliptext.com/articles/neuropathic-pain) mediated by [microglia](https://bliptext.com/articles/microglia) [in vitro](https://bliptext.com/articles/in-vitro) and [in vivo](https://bliptext.com/articles/in-vivo).\nP2X₄ receptors are upregulated following injury.\nThis upregulation allows for increased activation of [p38 mitogen-activated protein kinases](https://bliptext.com/articles/p38-mitogen-activated-protein-kinases), thereby increasing the release of brain-derived neurotrophic factor ([BDNF](https://bliptext.com/articles/brain-derived-neurotrophic-factor)) from microglia.\nBDNF released from microglia induces neuronal hyperexcitability through interaction with the [TrkB receptor](https://bliptext.com/articles/trkb-receptor).\nMore importantly, recent work shows that P2X₄ receptor activation is not only necessary for neuropathic pain, but it is also sufficient to cause neuropathic pain.","current_revision":null,"created_by":"kACnuQmH5k9Nr5VNVEpVeg7XpvUmMctD","created_at":"2025-01-26T10:20:20.889Z","updated_at":"2025-01-26T10:20:20.889Z","search_vector":"'p2rx4':1","search_content":" \n \n\n# \n**P2X purinoceptor 4** is a [protein](https://bliptext.com/articles/protein) that in humans is encoded by the P2RX4 [gene](https://bliptext.com/articles/gene).\nP2X purinoceptor 4 is a member of the [P2X receptor](https://bliptext.com/articles/p2x-purinoreceptor) family.\nP2X receptors are [trimeric](https://bliptext.com/articles/protein-trimer) protein complexes that can be [homomeric](https://bliptext.com/articles/homomeric) or [heteromeric](https://bliptext.com/articles/heteromer).\nThese receptors are [ligand-gated cation channels](https://bliptext.com/articles/ligand-gated-ion-channel) that open in response to ATP binding.\nEach receptor subtype, determined by the subunit composition, varies in its affinity to ATP and [desensitization kinetics](https://bliptext.com/articles/receptor-ligand-kinetics).\nThe **P2X4 receptor** is the [homotrimer](https://bliptext.com/articles/homotrimer) composed of three P2X4 monomers.\nThey are nonselective cation channels with high [calcium](https://bliptext.com/articles/calcium) permeability, leading to the [depolarization](https://bliptext.com/articles/depolarization) of the cell membrane and the activation of various Ca2+-sensitive intracellular processes.\nThe P2X4 receptor is uniquely expressed on [lysosomal compartments](https://bliptext.com/articles/lysosome) as well as the [cell surface](https://bliptext.com/articles/cell-membrane).\nThe 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](https://bliptext.com/articles/bladder), [gastrointestinal tract](https://bliptext.com/articles/gastrointestinal-tract), [uterus](https://bliptext.com/articles/uterus), and [arteries](https://bliptext.com/articles/artery), in uterine [endometrium](https://bliptext.com/articles/endometrium), and in [fat cells](https://bliptext.com/articles/adipocyte).\nP2X 4 receptors have been implicated in the regulation of cardiac function, ATP-mediated [cell death](https://bliptext.com/articles/apoptosis), [synaptic strengthening](https://bliptext.com/articles/long-term-potentiation), and activating of the [inflammasome](https://bliptext.com/articles/inflammasome) in response to injury.\n\n# Structure\nP2X receptors are composed of three subunits that can be homomeric or heteromeric by nature.\nIn mammals, there are seven different subunits, each encoded in a different gene (P2RX1-P2RX7).\nEach subunit has two [transmembrane](https://bliptext.com/articles/transmembrane-domain) [alpha helices](https://bliptext.com/articles/alpha-helix) (TM1 and TM2) linked by a large extracellular loop.\nAnalysis of [x-ray crystallographic](https://bliptext.com/articles/x-ray-crystallography) structures revealed a 'dolphin-like' [tertiary structure](https://bliptext.com/articles/protein-tertiary-structure), where the 'tail' is embedded in the [phospholipid bilayer](https://bliptext.com/articles/lipid-bilayer) and the upper and lower [ectodomains](https://bliptext.com/articles/ectodomain) form the 'head' and 'body' respectively.\nAdjacent interfaces of the subunits form a deep binding pocket for ATP.\nATP binding to these [orthosteric](https://bliptext.com/articles/allosteric-regulation) sites causes a shift in [conformation](https://bliptext.com/articles/conformational-change) opening the channel pore.\nThe P2X 4 subunits can form homomeric or heteromeric receptors.\nIn 2009, the first purinergic receptor crystallized was the closed state homomeric [zebrafish](https://bliptext.com/articles/zebrafish) P2X 4 receptor.\nAlthough truncated at its [N-](https://bliptext.com/articles/n-terminus) and [C- termini](https://bliptext.com/articles/c-terminus), this [crystal structure](https://bliptext.com/articles/crystal-structure) resolved and confirmed that these proteins were indeed [trimers](https://bliptext.com/articles/trimer-chemistry) with an ectodomain rich with [disulfide bonds](https://bliptext.com/articles/disulfide).\n# [Ribbon structures of (A) the P2X4 homotrimeric receptor and (B) the subunit monomer | upload.wikimedia.org/wikipedia/commons/4/4c/P2X4///receptor///open///state///and///monomer.jpg]\n\n# Gating mechanism\nP2X receptors have three confirmed conformational states: ATP-unbound closed, ATP-bound open, and ATP-bound desensitized.\nImaging of the human P2X3 and rat P2X7 receptors has revealed structural similarities and differences in their cytoplasmic domains.\nIn the ATP-bound state, both receptor types form [beta sheet](https://bliptext.com/articles/beta-sheet) structures from N- and C- termini of adjacent subunits.\nThese newly folded [secondary structures](https://bliptext.com/articles/protein-secondary-structure) come together to form a 'cytoplasmic cap' that helps stabilize the open pore.\nCrystal structures of the desensitized receptor no longer exhibit the cytoplasmic cap.\n# [Schematic of the P2X4 receptor conformational states | upload.wikimedia.org/wikipedia/commons/d/de/P2X4///hypothetical///gating///cycle.jpg]\n\n## Desensitization\n[Electrophysiology](https://bliptext.com/articles/electrophysiology) studies have revealed differences in the rates of receptor desensitization between different P2X subtypes.\n[Homotrimers](https://bliptext.com/articles/homotrimer) P2X1 and P2X3 are the fastest, with desensitization observed milliseconds after activation, while P2X2 and P2X4 receptors are on the timescale of seconds.\nNotably, the P2X7 receptor uniquely does not undergo desensitization.\nMutational studies working with the rat P2X2 and P2X3 receptors have identified three [residues](https://bliptext.com/articles/residue-biochemistry) in the N-terminus that majorly contribute to these differences.\nBy changing the [amino acids](https://bliptext.com/articles/amino-acid) in the P2X3 to match the analogous P2X2, the desensitization rate slowed down.\nConversely, changing residues of P2X2 to match P2X3 increased the desensitization rate.\nIn combination with the open state crystal structures, it was hypothesized that the cytoplasmic cap was stabilizing the open pore conformation.\nAdditionally, structural analysis of the open P2X3 receptor revealed transient changes in TM2, the transmembrane alpha helix lining the pore.\nWhile in the open state conformation, a small mid-region of TM2 develops into a [310-helix](https://bliptext.com/articles/310-helix).\nThis helical structure disappears with desensitization and instead TM2 reforms as a complete alpha helix repositioned closer to the extracellular side.\nThe helical recoil model uses the observed structural changes in TM2 and the transient formation of the cytoplasmic cap to describe a possible mechanism for the desensitization of P2X receptors.\nIn this model, it is theorized that the cytoplasmic cap fixes the intracellular end of the TM2 helix while stretching its extracellular end to allow ion influx.\nThis would induce the observed 310-helix.\nThe cap then disassembles and releases its hold on TM2 causing the helix to recoil towards the outer leaflet of the membrane.\nIn support of this theory, the P2X7 uniquely has a large cytoplasmic domain with [palmitoylated](https://bliptext.com/articles/palmitoylation) [C-cysteine anchor](https://bliptext.com/articles/lipid-anchored-protein) sites.\nThese sites further stabilize its cytoplasmic cap by anchoring the domain into the surrounding inner leaflet.\nMutations of the associated palmitoylation site residues cause observed atypical desensitization of the receptor.\n\n# Receptor trafficking\nP2X4 receptors are functionally expressed on both the cell surface and in lysosomes.\nAlthough preferentially localized and stored in [lysosomes](https://bliptext.com/articles/lysosome), P2X4 receptors are brought to the cell surface in response to extracellular signals.\nThese signals include [IFN-γ](https://bliptext.com/articles/interferon-gamma), [[CCL2](https://bliptext.com/articles/ccl2)1](https://bliptext.com/articles/ccl21), [CCL2](https://bliptext.com/articles/ccl2).\n[Fibronectin](https://bliptext.com/articles/fibronectin) is also involved in upregulation of P2X 4 receptors through interactions with [integrins](https://bliptext.com/articles/integrin) that lead to the activation of [SRC-family kinase](https://bliptext.com/articles/src-gene) member, [Lyn](https://bliptext.com/articles/lyn).\nLyn then activates [PI3K-AKT](https://bliptext.com/articles/pi3k-akt-mtor-pathway) and [MEK-ERK](https://bliptext.com/articles/mapk-erk) signaling pathways to stimulate receptor trafficking.\nInternalization of P2X 4 receptors is [clathrin](https://bliptext.com/articles/clathrin)- and [dynamin](https://bliptext.com/articles/dynamin)-dependent [endocytosis](https://bliptext.com/articles/endocytosis).\n\n# Pharmacology\n\n## Agonists\nP2X 4 receptors respond to ATP, but not αβmeATP.\nThese receptors are also potentiated by [ivermectin](https://bliptext.com/articles/ivermectin), cibacron blue, and [zinc](https://bliptext.com/articles/zinc).\n\n## Antagonists\nThe main pharmacological distinction between the members of the [purinoceptor](https://bliptext.com/articles/purinergic-receptor) family is the relative sensitivity to the antagonists [suramin](https://bliptext.com/articles/suramin) and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid ([PPADS](https://bliptext.com/articles/ppads)).\nThe product of this gene has the lowest sensitivity for these antagonists\n\n# Neuropathic pain\nThe P2X 4 receptor has been linked to [neuropathic pain](https://bliptext.com/articles/neuropathic-pain) mediated by [microglia](https://bliptext.com/articles/microglia) [in vitro](https://bliptext.com/articles/in-vitro) and [in vivo](https://bliptext.com/articles/in-vivo).\nP2X 4 receptors are upregulated following injury.\nThis upregulation allows for increased activation of [p38 mitogen-activated protein kinases](https://bliptext.com/articles/p38-mitogen-activated-protein-kinases), thereby increasing the release of brain-derived neurotrophic factor ([BDNF](https://bliptext.com/articles/brain-derived-neurotrophic-factor)) from microglia.\nBDNF released from microglia induces neuronal hyperexcitability through interaction with the [TrkB receptor](https://bliptext.com/articles/trkb-receptor).\nMore importantly, recent work shows that P2X 4 receptor activation is not only necessary for neuropathic pain, but it is also sufficient to cause neuropathic pain.","revisionCount":0},"hasMore":false,"nextCursor":null}

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