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1.A.7 ATP-gated P2X Receptor Cation Channel (P2X Receptor) Family

Members of the P2X Receptor family respond to ATP, a functional neurotransmitter released by exocytosis from many types of neurons. They have been placed into seven groups (P2X1 - P2X7) based on their pharmacological properties. These channels, which function at neuron-neuron and neuron-smooth muscle junctions, may play roles in the control of blood pressure and pain sensation. Their structural-fuctional relationships have been examined (Mager et al. 2004), and they are expressed throughout the body, mediating a multitude of functions, including muscle contraction, neuronal excitability and bone formation (Vial et al. 2004). They may function in lymphocyte and platelet physiology. They are found only in eukaryotes. Their ATP binding sites are extracellular and involve residues near ile-67. ATP binding causes the channel to go from the closed to the open state (Kracun et al., 2010). The intracellular amino terminus plays a dominant role in desensitization of P2X receptor ion channels (Allsopp and Evans, 2011). Activation and regulation of purinergic P2X receptor channels has been reviewed by Caddou et al. (2011). The gating mechanism has been proposed (Du et al., 2012). The ion access pathway to the transmembrane pore in P2X receptor channels has been estimated (Kawate et al., 2011). P2X receptor channels show threefold symmetry in ionic charge selectivity and unitary conductance (Browne et al., 2011). The binding of ATP to trimeric P2X receptors (P2XR) causes an enlargement of the receptor extracellular vestibule, leading to opening of the cation-selective transmembrane pore, and specific roles of vestibule amino acid residues in receptor activation have been evaluated (Rokic et al. 2013).

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 (P2X7; Smart et al., 2003). 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. 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.

The zebrafish chalice-shaped, trimeric P2X(4) receptor (TC#1.A.7.1.4) is knit together by subunit-subunit contacts implicated in ion channel gating and receptor assembly. Extracellular domains, rich in beta-strands, have large acidic patches that may attract cations, through fenestrations, to vestibules near the ion channel. In the transmembrane pore, the 'gate' is defined by an approximately 8 Å slab of protein. There are three non-canonical, intersubunit ATP-binding sites. ATP binding may promote subunit rearrangement as well as ion channel opening (Kawate et al., 2009).

The P2X1 receptor is the dominant P2X type in smooth muscle neurons. P2X2/P2X3 heterooligomers mediate sensory signals in many other sensory neurons. P2X4 and P2X6 receptors are highly expressed in the central nervous system and probably form heterooligomers. P2X7 is expressed in cells of the immune system and of hematopoetic origin. These channels have a homo- or heterotrimeric architecture (Aschrafi et al., 2004). The carboxy termini influence the regulation of P2X1 receptors (Wen and Evans 2011). N,S-acetal juglone derivatives are inhibitors of the P2X7 receptor-promoted  inflammatory response (Pacheco et al. 2023). Neurosteroids are positive and negative allosteric modulators of ligand-gated ion channels such as the P2X receptor (Sivcev et al. 2023).

The proteins of the P2X Receptor family are quite similar in sequence, but they possess 380-1000 amino acyl residues per subunit with variability in length localized primarily to the C-terminal domains. They possess two transmembrane spanners, one about 30-50 residues from their N-termini, the other near residues 320-340. The extracellular receptor domains between these two spanners (typically of about 270 residues) are well conserved with several conserved glycyl residues and 10 conserved cysteyl residues. The hydrophilic C-termini vary in length. Like epithelial Na+ channel (ENaC) proteins (TC #1.A.6), they possess (a) N- and C-termini localized intracellularly, (b) two putative transmembrane spanners, (c) a large extracellular loop domain, and (d) many conserved extracellular cysteyl residues. P2X receptor channels are probably hetero- or homomultimers of several subunits and transport small monovalent cations (Me+ and Me++). Some transport Ca2+, and after prolonged exposure to ATP, various metabolites as noted above.

The three-dimensional structure of a P2X receptor is known (Burnstock and Kennedy, 2011). When ATP binds, the pore opens within milliseconds, allowing the cations to flow. P2X receptors are expressed in both central and peripheral neurons where they are involved in neuromuscular and synaptic neurotransmission and neuromodulation. They are also expressed in most types of nonneuronal cells and mediate a wide range of actions, such as contraction of smooth muscle, secretion and immunomodulation. Changes in the expression of P2X receptors have been characterized in many pathological conditions of the cardiovascular, gastrointestinal, respiratory, and urinogenital systems and in the brain and special senses. The therapeutic potential of P2X receptor agonists and antagonists is currently being investigated in a range of disorders, including chronic neuropathic and inflammatory pain, depression, cystic fibrosis, dry eye, irritable bowel syndrome, interstitial cystitis, dysfunctional urinary bladder, and cancer.

Hattori and Gouaux (2012) 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. In mammals, lithocholic acid inhibits P2X2 and potentiates P2X4 receptor channel gating (Sivcev et al. 2020).

Phosphoinositides modulate the functions of most P2X receptor channels in neurons and glia. A dual polybasic motif has been shown to determine phosphoinositide binding and regulation in members of the P2X channel family (Bernier et al., 2012). Modeling has provided insight into the ligand-binding properties of P2X receptors (Dal Ben et al. 2015). 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).

Cys loop, glutamate, and P2X receptors are ligand-gated ion channels (LGICs) with 5, 4, and 3 protomers, respectively. Agonists and competitive antagonists apparently induce opposite motions of the binding pocket (Du et al., 2012b). Agonists, usually small, induce closure of the binding pocket, leading to opening of the channel pore, whereas antagonists, usually large, induce opening of the binding pocket, thereby stabilizing the closed pore. Both P2XRs and 5-HT3Rs, are modulated by pharmacologically relevant concentrations of ethanol, with inhibition or stimulation of P2XR subtypes and stimulation of 5-HT3Rs, respectively (Davies et al. 2006).

The strong expression of ATP-gated P2X3 receptors by a subpopulation of sensory neurons indicates the important role of these membrane proteins in nociceptive signaling in health and disease, especially when the latter is accompanied by chronic pain syndromes. These receptors exist mainly as trimeric homomers, and, in part, as heteromers (assembly of two P2X3 subunits with one P2X2). Recent investigations have suggested distinct molecular determinants responsible for agonist binding and channel opening for transmembrane flux of sodium, calcium and potassium ions. Trimeric P2X3 receptors are rapidly activated by ATP and can be strongly desensitized in the continuous presence of the agonist. Endogenous substances, widely thought to be involved in triggering pain, especially in pathological conditions, can potently modulate the expression and function of P2X3 receptors, with differential changes in response amplitude, desensitization and recovery. Strong facilitation of P2X3 receptor function is induced by enodogenous substances like the neuropeptide calcitonin gene-related peptide and the neurotrophins nerve growth factor and brain-derived neurotrophic factor. These substances possess distinct mechanisms of action on P2X3 receptors, generally attributable to discrete phosphorylation of N- or C-terminal P2X3 domains (Fabbretti and Nistri, 2012).

Two structural classes of pore-opening mechanisms have been established: bending of pore-lining helices in the case of tetrameric cation channels, and tilting of such helices in mechanosensitive channels. Expansion of the gate region in the external pore in P2X receptors is accompanied by a narrowing of the inner pore, indicating that pore-forming helices straighten on ATP binding to open the channel (Li et al., 2010). This pore-opening mechanism has implications for the role of subunit interfaces in the gating mechanism and points to a role of the internal pore in ion permeation.  Amino terminal residues are involved in lipid, cholesterol and lipid raft regulation of P2X1 (Allsopp et al. 2010).

P2X2 has a voltage-dependent gating property even though it lacks a canonical voltage sensor. It is a trimer in which each subunit has two transmembrane helices and a large extracellular domain. The three inter-subunit ATP binding sites are linked to the pore forming transmembrane (TM) domains by beta-strands.  Structural rearrangements of the linker region of the P2X2 receptor channel are induced not only by ligand binding but also by membrane potential change (Keceli and Kubo 2014). Knowledge about P2X receptor activation, especially focusing on the mechanisms underlying ATP-binding, conformational changes in the extracellular domain, and channel gating and desensitization, has been reviewed (Kawate 2017).

Ectodomain shedding of integral membrane receptors results in the release of soluble molecules and modification of the transmembrane regions of these receptors to mediate or modulate extracellular and intracellular signalling. Ectodomain shedding is stimulated by a variety of mechanisms, including the activation of P2 receptors by extracellular nucleotides.  P2 receptor-mediated shedding involves P2 receptors, P2X7 (TC# 1.A.7.1.3) and P2Y2 (TC# 9.A.14.13.16), and the sheddases, ADAM10 (Meprin A, 701 aas and 2 TMSs, N- and C-termini; Q16820) and ADAM17 (Disintegrin, 824 aas and 2 TMSs near the N- and C-termini; P78536; see subfamily 2 in TC Family 9.B.87) (Pupovac and Sluyter 2016). 

The trimeric ATP-gated ion channel, the P2X receptor, has six TMSs, and three of them, the M2 helices, line the ion conduction pathway. Using molecular dynamics simulation, Li 2018 identified four conformational states of the TM domain that are associated with four types of packing between M2 helices. Packing in the extracellular half of the M2 helix produces closed conformations, while packing in the intracellular half produces both open and closed conformations. State transition is observed and supports a mechanism where iris-like twisting of the M2 helices switches the location of helical packing between the extracellular and intracellular halves of the helices. This twisting motion alters the position and orientation of residue side-chains relative to the pore and thereby influences the pore geometry and possibly ion permeation. Helical packing, on the other hand, may restrict the twisting motion and generate discrete conformational states (Li 2018). 

P2X7 receptors are exceptionally versatile: in their canonical role they act as ATP-gated calcium channels and facilitate calcium-signaling cascades, exerting control over the cell via calcium-encoded sensory proteins and transcription factor activation. P2X7 also mediates transmembrane pore formation to regulate cytokine release and facilitate extracellular communication, and when persistently stimulated by high extracellular ATP levels, large P2X7 pores form, which induce apoptotic cell death through cytosolic ion dysregulation. As a scavenger receptor, P2X7 directly facilitates phagocytosis of the cellular debris that arises during neurogenesis (Leeson et al. 2019). P2X7 receptors amplify CNS damage in neurodegenerative diseases (Illes 2020).

In response to extracellular ATP, the purinergic receptor P2X7 mediates various biological processes, including phosphatidylserine (PtdSer) exposure, phospholipid scrambling, dye uptake, ion transport, and interleukin (IL)-1beta production. A transmembrane protein, 'Essential for reactive oxygen species' (Eros) is a necessary protein for P2X7 expression (Ryoden et al. 2020). An Eros-null mouse T cell line lost the ability to expose PtdSer, to scramble phospholipids, and to internalize a dye, YO-PRO-1, and Ca2+. The eros-null mutation abolished the ability of macrophages to secrete IL-1beta in response to ATP. Eros is localized to the endoplasmic reticulum and functions as a chaperone for NADPH oxidase components. Similarly, Eros at the endoplasmic reticulum transiently associates with P2X7 to promote the formation of a stable homotrimeric complex of P2X7. Thus, Eros acts as a chaperone not only for NADPH oxidase, but also for P2X7, and it contributes to the innate immune reaction (Ryoden et al. 2020).

The known seven mammalian receptor (R) subunits (P2X1-7) form cationic channels gated by ATP. Three subunits compose a receptor-channel. Each subunit is a polypeptide consisting of two TMSs (TMS1 and TMS2), intracellular N- and C-termini, and a bulky extracellular loop. Crystallization allowed the identification of the 3D-structure and gating cycle of P2XRs (Illes et al. 2020). The agonist binding pocket is located at the intersection of two neighboring subunits. In addition to the mammalian P2XRs, their primitive ligand-gated counterparts with little structural similarity have been cloned. Medicinal chemistry supplied a range of subtype selective antagonists as well as positive and negative allosteric modulators. Knockout mice and selective antagonists helped to identify pathological functions due to defective P2XRs, such as male infertility (P2X1), hearing loss (P2X2), pain/cough (P2X3), neuropathic pain (P2X4), inflammatory bone loss (P2X5), and faulty immune reactions (P2X7) (Illes et al. 2020). P2X6 acts as a physiological regulator of P2X4 receptor functions when the two receptors form heteroreceptors (Padilla et al. 2016). Also, P2X2/P2X4/P2X6 heterotrimeric receptors can occur (Antonio et al. 2014).

Seven subtypes of P2X receptor channels have been identified in mammals that can form both homomeric and heteromeric channels. P2X1-4 and P2X7 receptor channels are cation-selective, whereas P2X5 has been reported to have both cation and anion permeability. P2X receptor channel structures reveal that each subunit is comprised of two transmembrane helices, with both N-and C-termini on the intracellular side of the membrane and a large extracellular domain that contains the ATP binding sites at subunit interfaces. Structures of ATP-bound P2X receptors with the activation gate open revealed the presence of a cytoplasmic cap over the central ion permeation pathway, leaving lateral fenestrations that may be largely buried within the membrane as potential pathways for ions to permeate the intracellular end of the pore. Tam et al. 2023 identified a critical residue within the intracellular lateral fenestrations that is readily accessible to thiol-reactive compounds from both sides of the membrane and where substitutions influence the relative permeability of the channel to cations and anions. Thus, ions can enter or exit the internal pore through lateral fenestrations that play a critical role in determining the ion selectivity of P2X receptor channels.

Macropore formation and current facilitation are intriguing phenomena associated with ATP-gated P2X7 receptors (P2X7). Macropores are large pores formed in the cell membrane that allow the passage of large molecules. Evidence suggests two alternative pathways: direct entry through the P2X7 pore itself, and an indirect pathway triggered by P2X7 activation involving additional proteins, such as TMEM16F channel/scramblase. On the other hand, current facilitation refers to the progressive increase in current amplitude and activation kinetics observed with prolonged or repetitive exposure to ATP. Various mechanisms, including the activation of chloride channels and intrinsic properties of P2X7, have been proposed to explain this phenomenon. Cevoli et al. 2023 presented an overview of P2X7 current facilitation and macropore formation, proposing mechanistic models that may offer fresh insights into these processes.

The generalized transport reaction is:

Me+ (out) Me+ (in).

This family belongs to the: ENaC/P2X Superfamily.

References associated with 1.A.7 family:

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