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1.A.7.1.3
ATP-gated NaCl-regulated nonselective cation (Na+, K+ and Ca2+) channel, the P2X purinoreceptor 7, P2X7. It expands to accommodate large molecules such as NAD, N-methyl-D-glucamine and triethyl ammonium) (Li et al., 2005; Lu et al., 2007) and plays a role in changing pain thresholds. A region called ADSEG in all P2X receptors is located in the M2 domain which aligns with TMS 5 in VIC Kchannels (1.A.1). ADSEG from P2X(7)R forms cation-selective channels in artificial lipid bilayers and biological membranes similar to those of the full length protein (de Souza et al., 2011). Channel activity is regulated by calmodulin (Roger et al., 2008).  P2XRs allow direct permeation of nanometer-sized dyes (Browne et al. 2013).  Macrophage P2X7 receptors are modulated in response to infection with Leishmania amazonensis so that they become more permeable to anions and less permeable to cations (Marques-da-Silva et al. 2011).  Residues involved in pore conductivity and agonist sensitivity have been identified (Jindrichova et al. 2015) as have residues involved in channel activation (Caseley et al. 2016). The channel opening extends from the pre-TMS2 region through the outer half of the trihelical TMS2 channel; the gate and the selectivity filter have been identified (Pippel et al. 2017). The purinergic receptors, P2RX4 and P2RX7, when mutated, affect susceptibility to multiple sclerosis (MS) (Sadovnick et al. 2017). P2X7 may serve as a receptor for the regulation of annexin secretion during macrophage polarization (de Torre-Minguela et al. 2016). These receptors can reduce salivary gland inflammation (Khalafalla et al. 2017). The P2X7 receptor forms ion channels dependent on lipids but independently of its cytoplasmic domain (Karasawa et al. 2017).  A truncated naturally occurring variant of P2X7, P2X7-j of 258 aas, lacks the entire intracellular carboxyl terminus, the second TMS, and the distal third of the extracellular loops of the full-length P2X7 receptor. P2X7-j, expressed in the plasma membrane, failed to form pores and mediate apoptosis (Feng et al. 2006). P2X7-j formed heterooligomers with and blocked P2X7-mediated channel formation. Alternative splicing of P2X7 controls gating of the ion channel by ADP-ribosylation (Schwarz et al. 2012). Three distinct roles for P2X7 during adult neurogenesis have been demonstrated, and these depend on the extracellular ATP concentrations: (i) P2X7 receptors can form transmembrane pores leading to cell death, (ii) P2X7 receptors can regulate rates of proliferation, likely via calcium signalling, and (iii) P2X7 can function as scavenger receptors in the absence of ATP, allowing neural progenitor cells (NPCs) to phagocytose apoptotic NPCs during neurogenesis (Leeson et al. 2018). P2X7 also plays a role in purinergic vasotoxicity and cell death (Shibata et al. 2018). NAD+ covalently modifies the P2X7R of mouse T lymphocytes, thus lowering the ATP threshold for activation. Other structurally unrelated agents have been reported to activate  P2X7R: (a) the antibiotic polymyxin B, possibly a positive allosteric P2X7R modulator, (b) the bactericidal peptide LL-37, (c) the amyloidogenic β peptide, and (d) serum amyloid A (Di Virgilio et al. 2018). Some agents, such as Alu-RNA, have been suggested to activate P2X7R, acting on the intracellular N- or C-terminal domains. P2X7R of enteric neurons may be involved in diabetes-induced nitrous oxide (NOS) neuron damage via combining with pannexin-1 to form transmembrane pores which transport macromolecular substances and calcium into the cells (Zhang et al. 2019). ATP-gated P2X7 receptors require chloride channels to promote inflammation in human macrophages (Janks et al. 2019). P2X7 overexpression is can be associated with cancer progression. P2X7 plays also an important role in glioma biology (Matyƛniak et al. 2020). Upon activation by its main ligand, extracellular ATP, P2X7 can form a nonselective channel for cations to enter the cell, but prolonged activation, via high levels of extracellular ATP over an extended time period can lead to the formation of a macropore, leading to depolarization of the plasma membrane and ultimately to cell death. Thus, dependent on its activation state, P2X7 can either drive cell survival and proliferation, or induce cell death. It is relevant to cancerous growth (Lara et al. 2020). The human P2X7 receptor is a ligand gated ion channel opened by binding of ATP, like the other P2X receptor subtypes. P2X7 receptors become activated under pathological conditions of ATP release like hypoxia or cell destruction. They are involved in inflammatory and nociceptive reactions of the organism to these pathological events. Polar residues of the second TMS of the three protein subunits are important for ion conduction, with S342 constituting the ion selectivity filter and the gate of the channel. The specific long C-terminal domains are important for hP2X7 receptor ion channel function, as their loss strongly decreases ion channel currents (Markwardt 2020). Studies of the enhancement of P2X(7)-induced pore formation and apoptosis revealed an early effect of diabetes on retinal microvasculature; diabetes appears to facilitate the channel-to-pore transition that occurs during activation of these purinoceptors (Sugiyama et al. 2004).

Accession Number:Q99572
Protein Name:P2X purinoceptor 7 aka ATP receptor aka P2X7 aka Purinergic receptor aka P2Z receptor
Length:595
Molecular Weight:68586.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:3
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate sodium ions, calcium ions, inorganic cations

Cross database links:

RefSeq: NP_002553.2   
Entrez Gene ID: 5027   
Pfam: PF00864   
OMIM: 602566  gene
KEGG: hsa:5027   

Gene Ontology

GO:0032059 C:bleb
GO:0005737 C:cytoplasm
GO:0005887 C:integral to plasma membrane
GO:0005524 F:ATP binding
GO:0004931 F:extracellular ATP-gated cation channel acti...
GO:0001530 F:lipopolysaccharide binding
GO:0042803 F:protein homodimerization activity
GO:0001614 F:purinergic nucleotide receptor activity
GO:0005102 F:receptor binding
GO:0032060 P:bleb assembly
GO:0007166 P:cell surface receptor linked signaling pathway
GO:0045779 P:negative regulation of bone resorption
GO:0043409 P:negative regulation of MAPKKK cascade
GO:0046931 P:pore complex assembly
GO:0030501 P:positive regulation of bone mineralization
GO:0010524 P:positive regulation of calcium ion transpor...
GO:0045919 P:positive regulation of cytolysis
GO:0051495 P:positive regulation of cytoskeleton organiz...
GO:0050718 P:positive regulation of interleukin-1 beta s...
GO:0051709 P:regulation of killing of cells of another o...
GO:0002028 P:regulation of sodium ion transport
GO:0033198 P:response to ATP
GO:0019233 P:sensory perception of pain

References (7)

[1] “The permeabilizing ATP receptor, P2X7. Cloning and expression of a human cDNA.”  Rassendren F.et.al.   9038151
[2] “Gene structure and chromosomal localization of the human P2X7 receptor.”  Buell G.N.et.al.   9826911
[3] “The finished DNA sequence of human chromosome 12.”  Scherer S.E.et.al.   16541075
[4] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[5] “Proteomic and functional evidence for a P2X7 receptor signalling complex.”  Kim M.et.al.   11707406
[6] “A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor.”  Gu B.J.et.al.   11150303
[7] “The consensus coding sequences of human breast and colorectal cancers.”  Sjoeblom T.et.al.   16959974

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MPACCSCSDV FQYETNKVTR IQSMNYGTIK WFFHVIIFSY VCFALVSDKL YQRKEPVISS 
61:	VHTKVKGIAE VKEEIVENGV KKLVHSVFDT ADYTFPLQGN SFFVMTNFLK TEGQEQRLCP 
121:	EYPTRRTLCS SDRGCKKGWM DPQSKGIQTG RCVVYEGNQK TCEVSAWCPI EAVEEAPRPA 
181:	LLNSAENFTV LIKNNIDFPG HNYTTRNILP GLNITCTFHK TQNPQCPIFR LGDIFRETGD 
241:	NFSDVAIQGG IMGIEIYWDC NLDRWFHHCR PKYSFRRLDD KTTNVSLYPG YNFRYAKYYK 
301:	ENNVEKRTLI KVFGIRFDIL VFGTGGKFDI IQLVVYIGST LSYFGLAAVF IDFLIDTYSS 
361:	NCCRSHIYPW CKCCQPCVVN EYYYRKKCES IVEPKPTLKY VSFVDESHIR MVNQQLLGRS 
421:	LQDVKGQEVP RPAMDFTDLS RLPLALHDTP PIPGQPEEIQ LLRKEATPRS RDSPVWCQCG 
481:	SCLPSQLPES HRCLEELCCR KKPGACITTS ELFRKLVLSR HVLQFLLLYQ EPLLALDVDS 
541:	TNSRLRHCAY RCYATWRFGS QDMADFANLP SCCRWRIRKE FPKSEGQYSG FKSPY