P2X purinoreceptor

Last updated
ATP P2X receptor
SchematicP2XRSubunitV2.png
Figure 1. Schematic representation showing the membrane topology of a typical P2X receptor subunit. First and second transmembrane domains are labeled TM1 and TM2.
Identifiers
SymbolP2X_receptor
Pfam PF00864
InterPro IPR001429
PROSITE PDOC00932
TCDB 1.A.7
OPM superfamily 181
OPM protein 3h9v
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

The P2X receptors, also ATP-gated P2X receptor cation channel family, [1] 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). They belong to a larger family of receptors known as the ENaC/P2X superfamily. [1] ENaC and P2X receptors have similar 3-D structures and are homologous. [2] P2X receptors are present in a diverse array of organisms including humans, mouse, rat, rabbit, chicken, zebrafish, bullfrog, fluke, and amoeba. [3]

Contents

Figure 2. Crystal structure of the zebrafish P2X4 receptor (deltaP2X4-B) channel as viewed from the side (left), extracellular (top right), and intracellular (bottom right) perspectives(PDB: 3I5D ) FullStructureV2.png
Figure 2. Crystal structure of the zebrafish P2X4 receptor (deltaP2X4-B) channel as viewed from the side (left), extracellular (top right), and intracellular (bottom right) perspectives( PDB: 3I5D ​)

Physiological roles

P2X receptors are involved in a variety of physiological processes, [3] [4] including:

Tissue distribution

P2X receptors are expressed in cells from a wide variety of animal tissues. On presynaptic and postsynaptic nerve terminals and glial cells throughout the central, peripheral and autonomic nervous systems, P2X receptors have been shown to modulate synaptic transmission. [3] [12] Furthermore, P2X receptors are able to initiate contraction in cells of the heart muscle, skeletal muscle, and various smooth muscle tissues, including that of the vasculature, vas deferens and urinary bladder. P2X receptors are also expressed on leukocytes, including lymphocytes and macrophages, and are present on blood platelets. There is some degree of subtype specificity as to which P2X receptor subtypes are expressed on specific cell types, with P2X1 receptors being particularly prominent in smooth muscle cells, and P2X2 being widespread throughout the autonomic nervous system. However, such trends are very general and there is considerable overlap in subunit distribution, with most cell types expressing more than one subunits. For example, P2X2 and P2X3 subunits are commonly found co-expressed in sensory neurons, where they often co-assemble into functional P2X2/3 receptors.

Basic structure and nomenclature

To date, seven separate genes coding for P2X subunits have been identified, and named as P2X1 through P2X7, based on their pharmacological properties. [3] [13]

receptor subtype HGNC gene name chromosomal location
P2X1 P2RX1 17p13.3
P2X2 P2RX2 12q24.33
P2X3 P2RX3 11q12
P2X4 P2RX4 12q24.32
P2X5 P2RX5 17p13.3
P2X6 P2RX6 22p11.21
P2X7 P2RX7 12q24.31

The proteins of the P2X receptors are quite similar in sequence (>35% identity), but they possess 380-1000 amino acyl residues per subunit with variability in length. The subunits all share a common topology, possessing two transmembrane domains (one about 30-50 residues from their N-termini, the other near residues 320-340), a large extracellular loop and intracellular carboxyl and amino termini (Figure 1) [3] The extracellular receptor domains between these two segments (of about 270 residues) are well conserved with several conserved glycyl residues and 10 conserved cysteyl residues. The amino termini contain a consensus site for protein kinase C phosphorylation, indicating that the phosphorylation state of P2X subunits may be involved in receptor functioning. [14] Additionally, there is a great deal of variability (25 to 240 residues) in the C termini, indicating that they might serve subunit specific properties. [15]

Generally speaking, most subunits can form functional homomeric or heteromeric receptors. [16] Receptor nomenclature dictates that naming is determined by the constituent subunits; e.g. a homomeric P2X receptor made up of only P2X1 subunits is called a P2X1 receptor, and a heteromeric receptor containing P2X2 and P2X3 subunits is called a P2X2/3 receptor. The general consensus is that P2X6 cannot form a functional homomeric receptor and that P2X7 cannot form a functional heteromeric receptor. [17] [18]

Topologically, they resemble the epithelial Na+ channel proteins in possessing (a) N- and C-termini localized intracellularly, (b) two putative transmembrane segments, (c) a large extracellular loop domain, and (d) many conserved extracellular cysteyl residues. P2X receptor channels transport small monovalent cations, although some also transport Ca2+. [19]

Evidence from early molecular biological and functional studies has strongly indicated that the functional P2X receptor protein is a trimer, with the three peptide subunits arranged around an ion-permeable channel pore. [20] This view was recently confirmed by the use of X-ray crystallography to resolve the three-dimensional structure of the zebrafish P2X4 receptor [21] (Figure 2). These findings indicate that the second transmembrane domain of each subunit lines the ion-conducting pore and is therefore responsible for channel gating. [22]

The relationship between the structure and function of P2X receptors has been the subject of considerable research using site-directed mutagenesis and chimeric channels, and key protein domains responsible for regulating ATP binding, ion permeation, pore dilation and desensitization have been identified. [23] [24]

Activation and channel opening

Three ATP molecules are thought to be required to activate a P2X receptor, suggesting that ATP needs to bind to each of the three subunits in order to open the channel pore, though recent evidence suggests that ATP binds at the three subunit interfaces. [25] [26] Once ATP binds to the extracellular loop of the P2X receptor, it evokes a conformational change in the structure of the ion channel that results in the opening of the ion-permeable pore. The most commonly accepted theory of channel opening involves the rotation and separation of the second transmembrane domain (TM) helices, allowing cations such as Na+ and Ca2+ to access the ion-conducting pore through three lateral fenestrations above the TM domains. [27] [28] The entry of cations leads to the depolarization of the cell membrane and the activation of various Ca2+-sensitive intracellular processes. [29] [30] The channel opening time is dependent upon the subunit makeup of the receptor. For example, P2X1 and P2X3 receptors desensitize rapidly (a few hundred milliseconds) in the continued presence of ATP, whereas the P2X2 receptor channel remains open for as long as ATP is bound to it.

Transport reaction

The generalized transport reaction is:

Monovalent cations or Ca2+ (out) ⇌ monovalent cations or Ca2+ (in)

Pharmacology

The pharmacology of a given P2X receptor is largely determined by its subunit makeup. [13] Different subunits exhibit different sensitivities to purinergic agonists such as ATP, α,β-meATP and BzATP; and antagonists such as pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) and suramin. [3] Of continuing interest is the fact that some P2X receptors (P2X2, P2X4, human P2X5, and P2X7) exhibit multiple open states in response to ATP, characterized by a time-dependent increase in the permeabilities of large organic ions such as N-methyl-D-glucamine (NMDG+) and nucleotide binding dyes such as propidium iodide (YO-PRO-1). Whether this change in permeability is due to a widening of the P2X receptor channel pore itself or the opening of a separate ion-permeable pore is the subject of continued investigation. [3]

Synthesis and trafficking

P2X receptors are synthesized in the rough endoplasmic reticulum. After complex glycosylation in the Golgi apparatus, they are transported to the plasma membrane, whereby docking is achieved through specific members of the SNARE protein family. [16] A YXXXK motif in the C terminus is common to all P2X subunits and seems to be important for trafficking and stabilization of P2X receptors in the membrane. [31] Removal of P2X receptors occurs via clathrin-mediated endocytosis of receptors to endosomes where they are sorted into vesicles for degradation or recycling. [32]

Allosteric modulation

The sensitivity of P2X receptors to ATP is strongly modulated by changes in extracellular pH and by the presence of heavy metals (e.g. zinc and cadmium). For example, the ATP sensitivity of P2X1, P2X3 and P2X4 receptors is attenuated when the extracellular pH<7, whereas the ATP sensitivity of P2X2 is significantly increased. On the other hand, zinc potentiates ATP-gated currents through P2X2, P2X3 and P2X4, and inhibits currents through P2X1. The allosteric modulation of P2X receptors by pH and metals appears to be conferred by the presence of histidine side chains in the extracellular domain. [3] In contrast to the other members of the P2X receptor family, P2X4 receptors are also very sensitive to modulation by the macrocyclic lactone, ivermectin. [33] Ivermectin potentiates ATP-gated currents through P2X4 receptors by increasing the open probability of the channel in the presence of ATP, which it appears to do by interacting with the transmembrane domains from within the lipid bilayer. [34]

Subfamilies

Human proteins containing this domain

P2RX1; P2RX2; P2RX3; P2RX4; P2RX5; P2RX7; P2RXL1; TAX1BP3

See also

Related Research Articles

<span class="mw-page-title-main">Ion channel</span> Pore-forming membrane protein

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

<span class="mw-page-title-main">Voltage-gated ion channel</span> Type of ion channel transmembrane protein

Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in a cell's electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing. Cell membranes are generally impermeable to ions, thus they must diffuse through the membrane through transmembrane protein channels.

<span class="mw-page-title-main">Cyclic nucleotide–gated ion channel</span> Family of transport proteins

Cyclic nucleotide–gated ion channels or CNG channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various tissue and cell types, and are significant in sensory transduction as well as cellular development. Their function can be the result of a combination of the binding of cyclic nucleotides and either a depolarization or a hyperpolarization event. Initially discovered in the cells that make up the retina of the eye, CNG channels have been found in many different cell types across both the animal and the plant kingdoms. CNG channels have a very complex structure with various subunits and domains that play a critical role in their function. CNG channels are significant in the function of various sensory pathways including vision and olfaction, as well as in other key cellular functions such as hormone release and chemotaxis. CNG channels have also been found to exist in prokaryotes, including many spirochaeta, though their precise role in bacterial physiology remains unknown.

<span class="mw-page-title-main">Ligand-gated ion channel</span> Type of ion channel transmembrane protein

Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

<span class="mw-page-title-main">Chloride channel</span> Class of transport proteins

Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration in vivo is much higher than other anions. Several families of voltage-gated channels and ligand-gated channels have been characterized in humans.

<span class="mw-page-title-main">Sodium channel</span> Transmembrane protein allowing sodium ions in and out

Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels.

<span class="mw-page-title-main">Purinergic receptor</span> Family of cell membrane receptors in almost all tissues

Purinergic receptors, also known as purinoceptors, are a family of plasma membrane molecules that are found in almost all mammalian tissues. Within the field of purinergic signalling, these receptors have been implicated in learning and memory, locomotor and feeding behavior, and sleep. More specifically, they are involved in several cellular functions, including proliferation and migration of neural stem cells, vascular reactivity, apoptosis and cytokine secretion. These functions have not been well characterized and the effect of the extracellular microenvironment on their function is also poorly understood.

<span class="mw-page-title-main">Epithelial sodium channel</span> Group of membrane proteins

The epithelial sodium channel(ENaC), (also known as amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to sodium ions (Na+). It is assembled as a heterotrimer composed of three homologous subunits α or δ, β, and γ, These subunits are encoded by four genes: SCNN1A, SCNN1B, SCNN1G, and SCNN1D. The ENaC is involved primarily in the reabsorption of sodium ions at the collecting ducts of the kidney's nephrons. In addition to being implicated in diseases where fluid balance across epithelial membranes is perturbed, including pulmonary edema, cystic fibrosis, COPD and COVID-19, proteolyzed forms of ENaC function as the human salt taste receptor.

Two-pore channels (TPCs) are eukaryotic intracellular voltage-gated and ligand gated cation selective ion channels. There are two known paralogs in the human genome, TPC1s and TPC2s. In humans, TPC1s are sodium selective and TPC2s conduct sodium ions, calcium ions and possibly hydrogen ions. Plant TPC1s are non-selective channels. Expression of TPCs are found in both plant vacuoles and animal acidic organelles. These organelles consist of endosomes and lysosomes. TPCs are formed from two transmembrane non-equivalent tandem Shaker-like, pore-forming subunits, dimerized to form quasi-tetramers. Quasi-tetramers appear very similar to tetramers, but are not quite the same. Some key roles of TPCs include calcium dependent responses in muscle contraction(s), hormone secretion, fertilization, and differentiation. Disorders linked to TPCs include membrane trafficking, Parkinson's disease, Ebola, and fatty liver.

The Cys-loop ligand-gated ion channel superfamily is composed of nicotinic acetylcholine, GABAA, GABAA-ρ, glycine, 5-HT3, and zinc-activated (ZAC) receptors. These receptors are composed of five protein subunits which form a pentameric arrangement around a central pore. There are usually 2 alpha subunits and 3 other beta, gamma, or delta subunits (some consist of 5 alpha subunits). The name of the family refers to a characteristic loop formed by 13 highly conserved amino acids between two cysteine (Cys) residues, which form a disulfide bond near the N-terminal extracellular domain.

<span class="mw-page-title-main">P2Y receptor</span> Subclass of purinergic P2 receptors

P2Y receptors are a family of purinergic G protein-coupled receptors, stimulated by nucleotides such as adenosine triphosphate, adenosine diphosphate, uridine triphosphate, uridine diphosphate and UDP-glucose.To date, 8 P2Y receptors have been cloned in humans: P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13 and P2Y14.

<span class="mw-page-title-main">P2RX7</span> Protein-coding gene in the species Homo sapiens

P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.

<span class="mw-page-title-main">P2RX1</span> Protein-coding gene in the species Homo sapiens

P2X purinoceptor 1, also ATP receptor, is a protein that in humans is encoded by the P2RX1 gene.

<span class="mw-page-title-main">P2RX4</span> Protein-coding gene in the species Homo sapiens

P2X purinoceptor 4 is a protein that in humans is encoded by the P2RX4 gene. P2X purinoceptor 4 is a member of the P2X receptor family. P2X receptors are trimeric protein complexes that can be homomeric or heteromeric. These receptors are ligand-gated cation channels that open in response to ATP binding. Each receptor subtype, determined by the subunit composition, varies in its affinity to ATP and desensitization kinetics.

<span class="mw-page-title-main">P2RX5</span> Protein-coding gene in the species Homo sapiens

P2X purinoceptor 5 is a protein in humans that is encoded by the P2RX5 gene.

<span class="mw-page-title-main">P2RX2</span> Protein-coding gene in the species Homo sapiens

P2X purinoceptor 2 is a protein that in humans is encoded by the P2RX2 gene.

<span class="mw-page-title-main">P2RX3</span> Protein-coding gene in the species Homo sapiens

P2X purinoceptor 3 is a protein that in humans is encoded by the P2RX3 gene.

<span class="mw-page-title-main">P2RX6</span> Protein-coding gene in the species Homo sapiens

P2X purinoceptor 6 is a protein that in humans is encoded by the P2RX6 gene.

<span class="mw-page-title-main">Cell surface receptor</span> Class of ligand activated receptors localized in surface of plama cell membrane

Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.

<span class="mw-page-title-main">Acid-sensing ion channel</span> Class of transport proteins

Acid-sensing ion channels (ASICs) are neuronal voltage-insensitive sodium channels activated by extracellular protons permeable to Na+. ASIC1 also shows low Ca2+ permeability. ASIC proteins are a subfamily of the ENaC/Deg superfamily of ion channels. These genes have splice variants that encode for several isoforms that are marked by a suffix. In mammals, acid-sensing ion channels (ASIC) are encoded by five genes that produce ASIC protein subunits: ASIC1, ASIC2, ASIC3, ASIC4, and ASIC5. Three of these protein subunits assemble to form the ASIC, which can combine into both homotrimeric and heterotrimeric channels typically found in both the central nervous system and peripheral nervous system. However, the most common ASICs are ASIC1a and ASIC1a/2a and ASIC3. ASIC2b is non-functional on its own but modulates channel activity when participating in heteromultimers and ASIC4 has no known function. On a broad scale, ASICs are potential drug targets due to their involvement in pathological states such as retinal damage, seizures, and ischemic brain injury.

References

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  34. ↑ Priel A, Silberberg SD (2004). "Mechanism of ivermectin facilitation of human P2X4 receptor channels". J. Gen. Physiol. 123 (3): 281–93. doi:10.1085/jgp.200308986. PMC   2217454 . PMID   14769846.

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