The P2X receptors, also ATP-gated P2X receptor cation channel family, is a protein family that consists of cation-permeable ligand-gated ion channels that open in response to the binding of extracellular adenosine 5'-triphosphate (ATP) ^[1]. To date, seven separate genes coding for P2X subunits have been identified, and named as P2X1 through P2X7, based on their pharmacological properties ^[2].

The seven different P2X receptor types differ in their sensitivities to ATP and various ATP analogues as well as in their inactivation kinetics. ATP binding initially causes opening of the non-selective cation channel, allowing Ca²⁺ entry. Prolonged exposure of slowly inactivating forms to ATP leads to dilation of the pore, making it permeable to larger molecules (up to 1000 Da). Then it functions as a cytolytic pore that is permeable to organic cations such as ethidium and N-methyl-D-glucamine. Formation of this cytolytic pore is regulated by the C-terminal hydrophilic domain in at least one of these receptors. The ion-conducting pathway is formed by three TMS 2 (TMS2) alpha-helices, each being provided by the three subunits of the trimer. P2X receptors are trimeric ATP-activated ion channels permeable to Na⁺, K⁺, and Ca^{2+ [9]}. The seven P2X receptor subtypes are implicated in physiological processes that include modulation of synaptic transmission, contraction of smooth muscle, secretion of chemical transmitters and regulation of immune responses ^[10].

Each subunit of a trimeric P2X2 receptor is composed of intracellular N and C termini, a large extracellular domain containing the ATP binding site and 2 transmembrane helices (TM1 and TM2) that form a cation permeable pore. Whole-exome sequencing and linkage analysis have identified 3 hP2X2 receptor mutations (V60L, D273Y, and G353R) ^[4].

The main pharmacological distinction between the members of the purinoceptor family is the relative sensitivity to the antagonists suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). The product of this gene has the lowest sensitivity for these antagonists ^[8]. Gefapixant, sold under the brand name Lyfnua, is a medication used to treat chronic (long-term) cough. It acts as an antagonist of the P2RX3 receptor. JNJ-54175446 and JNJ-55308942 are selective antagonists. The residues of Lys-70, Asp-170, Lys-190, and Lys-249 (orange sphere in the 3D structure viewer) are definied the antagonist site for PPADS binding ^[8]. The residues Phe48, Val43 and Tyr42 (black sphere in the 3D structure viewer) of P2X4 transmembrane domain-1 are important for potentiating effect of lithocholic acid ^[7]. The most important aromatic residue is probably Y234 (yellow sphere in the 3D structure viewer). It is involved in ligand binding whilst mutation of the closely positioned Y240 does not have any significant effects ^[4].

Opiranserin is a selective and combined glycine GlyT2 transporter blocker (IC₅₀ = 0.86 μM), purine P2X3 receptor antagonist (IC₅₀ = 0.87 μM), and serotonin 5-HT2A receptor antagonist (IC₅₀ = 1.3 μM) which is under development by Vivozon for the intravenous treatment of postoperative pain ^{[9, 10]}. As of April 2017, it is in phase II clinical trials for this indication ^[11]. The P2X7 receptor current can be blocked by zinc, calcium, magnesium, and copper ^[12]. P2X7 receptors are sensitive to pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and relatively insensitive to suramin, but the suramin analog, NF279, is much more effective ^[13]. Oxidized ATP (OxATP) and Brilliant Blue G has also been used for blocking P2X7 in inflammation. Other blockers include the large organic cations calmidazolium (a calmodulin antagonist) and KN-62 (a CaM kinase II antagonist) ^[12].

Hattori and Gouaux reported the crystal structure of the zebrafish P2X(4) receptor in complex with ATP and a new structure of the apo receptor. The agonist-bound structure reveals an ATP-binding motif and an open ion channel. ATP binding induces cleft closure of the nucleotide-binding pocket, flexing of the lower body β-sheet and a radial expansion of the extracellular vestibule. The structural widening of the extracellular vestibule is directly coupled to the opening of the ion channel pore by way of an iris-like expansion of the transmembrane helices ^[3]. P2X4 receptors respond to ATP, but not αβ meATP^[14]. These receptors are also potentiated by ivermectin, cibacron blue, and zinc. P2X7 receptors respond to BzATP more readily than ATP. ADP and AMP are weak agonists of P2X7 receptors, but a brief exposure to ATP can increase their effectiveness ^[12]. Glutathione has been proposed to act as a P2X7 receptor agonist when present at milimolar levels, inducing calcium transients and GABA release from retinal cells ^{[15, 16]}. The residue of D273Y (green sphere in the 3D structure viewer), which is ATP binding site, mutation prevents the expression of functional channels on the cell membrane ^[4].

Most of the known P2XR antagonist classes are considered negative allosteric modulators (NAMs). The residues of F88A, T90V, D92A, F103A, and V312A (red sphere in the 3D structure viewer) are the key residue of allosteric pocket for ZINC58368839, brilliant blue G, KN-62, and calmidazolium ^[5]. Mutation of the conserved residues S60 and D318 (blue sphere in the 3D structure viewer) led to alterations in P2X7 response and a higher sensitivity to ATP in the absence of modulators suggesting residues in the connecting rods play an important role in regulating P2X7 gating ^[6].