1.A.7.1.3
ATP-gated NaCl-regulated nonselective cation (Na⁺, K⁺ and Ca²⁺) channel, the P2X purinoreceptor 7, P2X7, P2RX7 or P2X7R. 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 K⁺ channels (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 (Matyśniak 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). Regorafenib exhibits antitumor activity on the breast cancer cell line via modulation of the P2X7/HIF-1alpha/VEGF, P2X7/P38, P2X7/ERK/NF-kappaB, and P2X7/beclin 1 pathways (Salahuddin et al. 2021). The involvement of the P2RX7 purinoreceptor in triggering mitochondrial dysfunction during the development of neurodegenerative disorders has been reviewed (Zelentsova et al. 2022). The P2X7 receptor and purinergic signaling play roles in orchestrating mitochondrial dysfunction in neurodegenerative diseases (Zelentsova et al. 2022). The P2X7 purinergic receptor represents a potential target in heart diseases (Bin Dayel et al. 2023). Conserved and receptor specific TMS1 residues control surface expression of the P2X7 protein, nonpolar residues control receptor sensitization, and D48 regulates intrinsic channel properties (Rupert et al. 2023). The P2X7 receptor of microglia in the olfactory bulb mediates the pathogenesis of olfactory dysfunction in a mouse model of allergic rhinitis (Ren et al. 2023). P2RX7 variants interact with distal and more etiological stressors in influencing the severity of anxiety symptoms (Kristof et al. 2023). P2X7 receptor inhibition ameliorates ubiquitin-proteasome system dysfunction associated with Alzheimer's disease (Bianchi et al. 2023). P2X7R radioligands are reliable tools for the diagnosis of neuroinflammation in clinical studies, and detection and measurement of free P2X7 receptor (or the P2X7 subunit) in human blood suggested its potential use as a circulating marker of inflammation (Di Virgilio et al. 2023). There are  three frequent coding polymorphisms in the gene for the human P2X7 ion channel, and their functions are known (Schäfer et al. 2022). A P2X7 receptor blockade reduces pyroptotic inflammation and promotes phagocytosis in Vibrio vulnificus infection (Wann et al. 2023). Niemann-Pick disease type C is a rare autosomal recessive of lysosomal storage disorder characterized by impaired intracellular lipid transport and has a tendency to accumulate the fatty acids and glycosphingolipids in a variety of neurovisceral tissues, and the mutational impact in causing Niemann-Pick disease type C has been studied (Kannan et al. 2023). Receptor agonists and antagonists and other modulators of purinergic signalling have potential as novel therapeutics for a broad range of diseases and conditions. An up-to-date description of selected efforts to discover and develop new small molecular purinergic drugs has appeared (Jacobson and Salvemini 2023). Astrocytes induce ischemic tolerance via P2X7 receptor-mediated lactate release (Hirayama et al. 2024). P2X7 receptors in dendritic cells and macrophages have implications in antigen presentation and T lymphocyte activation (Acuña-Castillo et al. 2024).  Huang et al. demonstrate that the complex of sodium/potassium-transporting ATPase subunit alpha (NKAα1) and purinergic P2X7 receptor (P2X7R) maintains the resting state of microglial membranes. Stress increases free P2X7R that then binds to ATP to activate microglia, which may promote anxious behaviors (Fang and Lai 2024). High-affinity P2Y2 and low-affinity P2X7 receptors interact to modulate ATP-mediated calcium signaling in murine osteoblasts (Mikolajewicz et al. 2021).  Mutations in this purinergic ATP-dependent cation channel can give rise to chronic nonbacterial oteomyelitis (CNO) (Roberts et al. 2024). P2RX7 gene variants associate with altered inflammasome assembly and reduced pyroptosis in chronic nonbacterial osteomyelitis (CNO) (Charras et al. 2024).  P2 purinergic receptors are involved in the pathogenesis of pruritus, with several showing potential as novel therapeutic options for alleviating pruritus (Liu et al. 2025).  The P2X7 receptor plays a role in neuroinflammation in anxiety and depression (Kristof et al. 2025).