TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
*1.A.7.1.1









ATP-gated cation channel (purinoceptor or ATP-neuroreceptor). Residues Glu52-Gly96 play roles in agonist binding and channel gating (Allsopp et al., 2011).  The rat protein is 89% identical to the human ortholog. Mutations likely to confer ivermectin sensitivity to human P2X1 have been proposed (Pasqualetto et al. 2018).

Eukaryota
Metazoa
P2X1 of Homo sapiens
*1.A.7.1.2









ATP-gated cation channel (purinoceptor or ATP-neuroreceptor).  His33 and Ser345 are proximal to each other across an intra-subunit interface, and the relative movement between the two TMSs is likely important for transmitting the action of ATP binding to the opening of the channel (Liang et al. 2013).  Two processes contribute to receptor desensitization, one, bath calcium-independent and the other, bath calcium-dependent, the latter being more important (Coddou et al. 2015).  ATP dissociation causes reduction in outer pore expansion compared to the ATP-bound state. Moreover, the inner and outer ends of adjacent pore-lining helices come closer during opening, likely through a hinge-bending motion (Habermacher et al. 2016).

Eukaryota
Metazoa
P2X2 of Rattus norvegicus
*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). 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-TMS 2 region through the outer half of the trihelical TMS 2 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, lacked 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 gatin 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.

Eukaryota
Metazoa
P2X7 of Homo sapiens (Q99572)
*1.A.7.1.4









The P2X4 receptor (P2X4R) of the zebrafish of 389 aas and 2 TMSs. The 3-d structure is known in its closed, resting state (Kawate et al., 2009).  A hift of L340 packing between different sites may alter the side-chain orientation that frees or occludes the pore. L340, A344 and A347 may also gate the pore by a expansion-contraction mechanism (Li 2015). Ivermectin binds to the transmembrane domain while Zn2+ binds to the extracellular domain, but they exhbit additive cooperativity (Latapiat et al. 2017).

Eukaryota
Metazoa
P2X(4) purinoceptor (ATP) gated ionotropic receptor, subunit 4 of Danio rerio (Q98TZ0)
*1.A.7.1.5









The purinergic receptor, P2X4, is sensitive to the macrocyclic lactone, ivermectin, which allosterically modulates both ion conduction and channel gating (Samways et al., 2012). The gating mechanism has been discussed (Du et al., 2012) and considered to be determined by the conformation of the transmembrane domain (Minato et al. 2016; Pierdominici-Sottile et al. 2016). The crystal structure of the ATP-gated P2X(4) ion channel in the closed state has been reported (Kawate et al., 2009). Unobstructed lateral portals are preferentially used as access routes to the pores of P2X receptors (Samways et al., 2011).  Activation is ATP-dependent and rapid, but desensitization occurs within seconds and is ATP-independent (Stojilkovic et al. 2010). Ectodomain cysteines play roles in agonist binding and channel gating (Rokic et al. 2010).  Evermectin has distinct effects on opening and dilation of the channel pore, the first accounting for increased peak current amplitude, and the latter correlating with changes in the kinetics of receptor deactivation (Zemkova et al. 2014). Conserved amino acids within the regions linking the ectodomain with the pore-forming transmembrane domain may contribute to signal transduction and channel gating (Gao et al. 2015; Jelínkova et al. 2008). Binding of ATP produces distortions in the chains that eliminate restrictions on the interchain displacements, leading to the opening of the pore (Pierdominici-Sottile et al. 2016). The purinergic receptors, P2RX4 and P2RX7, affect susceptibility to multiple sclerosis (MS) (Sadovnick et al. 2017).

Eukaryota
Metazoa
P2X4 of Homo sapiens (Q99571)
*1.A.7.1.6









ATP-gated P2X3 receptor. Tyr-37 stabilizes desensitized states and restricts calcium permeability (Jindrichova et al., 2011).  Exhibits "high affinity desensitization" but slow reactivation from the desensitized state (Giniatullin and Nistri 2013). An endogenous regulator of P2X3 in bladder is the Pirt protein (TC#8.A.64.1.1) Gao et al. 2015).  X-ray crystal structures of the human P2X3 receptor in apo/resting, agonist-bound/open-pore, agonist-bound/closed-pore/desensitized and antagonist-bound/closed states have been determined (Mansoor et al. 2016). The open state structure harbours an intracellular motif termed the 'cytoplasmic cap', which stabilizes the open state of the ion channel pore and creates lateral, phospholipid-lined cytoplasmic fenestrations for water and ion egress.

Eukaryota
Metazoa
P2X3 receptor of Homo sapiens (P56373)
*1.A.7.1.7









P2X purinoceptor

Eukaryota
Metazoa
P2X purinoceptor of Tetaodon nigroviridis
*1.A.7.1.8









The p2X purinoreceptor 4a of 389 aas and 2 TMSs, P2X4a of 388 aas and 2 TMSs. A splice variant of 361 aas also exists and may form heterotrimers with P2RX4a (Townsend-Nicholson et al. 1999). Plays a role in alcoholism (Franklin et al. 2014). P2RX4 deficiency alleviates allergen-induced airway inflamation (Zech et al. 2016).

Eukaryota
Metazoa
P2X4a of Mus musculus (Mouse)
*1.A.7.1.9









Purinorepector, P2X7 (P2RX7) of 595 aas and 2 TMSs.  The crystal structure in complex with a series of allosteric antagonists were published, giving insight into the mechanism of channel antagonism (Pasqualetto et al. 2018).

Eukaryota
Metazoa
P2X7 of Ailuropoda melanoleuca (Giant panda)
*1.A.7.1.10









Green algal ATP-gated cation channel receptor P2X4 of 384 aas, 2 TMSs (Fountain et al., 2008).

Eukaryota
Viridiplantae
P2X4 of Ostreococcus lucimarinus
*1.A.7.2.1









The osmoregulatory intracellular P2X receptor, P2XA gated by ATP (present in the osmoreulatory organelle, the contractile vacuole) (Fountain et al., 2007). One of five P2X receptors in D. discoideum is localized to the contractile vacuole with the ligand binding domain facing the lumen. Plays a role in Ca2+ signaling, but also is Cl- permeable. May function in osmoregulation (Ludlow et al., 2009).  Four of the five receptors operate as ATP-gated channels (P2XA, P2XB, P2XD, and P2XE). For the P2XA receptor, ATP was the only effective agonist, but extracellular sodium, compared with potassium, strongly inhibited ATP responses in P2XB, P2XD, and P2XE receptors. Increasing the proton concentration (pH 6.2) accelerated desensitization at P2XA receptors and decreased currents at P2XD receptors, but increased the currents at P2XB and P2XE receptors. Dictyostelium lacking P2XA receptors showed an impaired regulatory volume decrease in hypotonic solution. This phenotype was rescued by overexpression of P2XA and P2XD receptors, partially rescued by P2XB and P2XE receptors, and not rescued by P2XC receptor which appeared to be inactive (Baines et al. 2013).

Eukaryota
Dictyosteliida
P2XA of Dictyostelium discoideum (Q55A88)
*1.A.7.2.2









Uncharacterized P2X recpetor of 399 aas and 2 TMSs/

Eukaryota
Cryptophyta
UP of Guillardia theta
*1.A.7.2.3









Uncharacterized P2X receptor of 524 aas and 2 TMSs.

Eukaryota
Isochrysidales
UP of Emiliania huxleyi (Pontosphaera huxleyi)
*1.A.7.2.4









Uncharacterized protein of 488 aas and 2 TMSs.

Eukaryota
Chromerida
UP of Vitrella brassicaformis