P2X Receptor
Encyclopedia
P2X receptors are a family 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 purinergic receptors. P2X receptors are present in a diverse array of organisms including humans, mouse, rat, rabbit, chicken, zebrafish, bullfrog, fluke, and amoeba.
The subunits all share a common topology, possessing two plasma membrane
spanning domains, a large extracellular loop and intracellular carboxyl
and amino
termini (Figure 1). With the exception of P2X6, each subunit can readily form a functional homomeric
receptor . 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 when expressed alone, but nevertheless can co-assemble with other subunits to form functional heteromeric receptors. Current data suggests that, all of the P2X subunits are capable of forming heteromeric P2X receptors with at least one other subunit type.
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. This view was recently confirmed by the use of X-ray crystallography
to resolve the three-dimensional structure of the zebrafish P2X4 receptor (Figure 2).
The relationship between the structure and function of P2X receptors has been the subject of considerable research, and key protein domains responsible for regulating ATP binding, ion permeation, pore dilation and desensitization have been identified.
) and suramin
. 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.
. On presynaptic and postsynaptic nerve terminals
throughout the central
, peripheral
and autonomic
nervous systems, P2X receptors have been shown to modulate synaptic transmission
. 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 platelet
s. 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 neuron
s, where they often co-assemble into functional P2X2/3 receptors.
in the structure of the ion channel that results in the opening of the ion-permeable pore. This allows cations such as Na+
and Ca2+
to enter the cell, leading to depolarization
of the cell membrane and the activation of various Ca2+-sensitive intracellular processes. 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. 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. The precise mechanism by which the binding of ATP leads to the opening of the P2X receptor channel pore is not well understood, but is currently under investigation.
; P2RX2
; P2RX3
; P2RX4
; P2RX5
; P2RX7
; P2RXL1; TAX1BP3
Ligand-gated ion channel
Ligand-gated ion channels are one type of ionotropic receptor or channel-linked receptor. They are a group of transmembrane ion channels that are opened or closed in response to the binding of a chemical messenger , such as a neurotransmitter.The binding site of endogenous ligands on LGICs...
that open in response to the binding of extracellular adenosine 5'-triphosphate (ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
). They belong to a larger family of receptors known as the purinergic receptors. P2X receptors are present in a diverse array of organisms including humans, mouse, rat, rabbit, chicken, zebrafish, bullfrog, fluke, and amoeba.
Basic structure and nomenclature
To date, seven separate genes coding for P2X subunits have been identified, and named to as P2X1 through P2X7.| receptor subtype | HUGO Human Genome Organisation The Human Genome Organisation is an organization involved in the Human Genome Project, a project about mapping the human genome. HUGO was established in 1989 as an international organization, primarily to foster collaboration between genome scientists around the world... gene name |
chromosomal location Locus (genetics) In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map... |
|---|---|---|
| P2X1 P2RX1 P2X purinoceptor 1 is a protein that in humans is encoded by the P2RX1 gene.... |
P2RX1 | 17p13.3 |
| P2X2 P2RX2 P2X purinoceptor 2 is a protein that in humans is encoded by the P2RX2 gene.... |
P2RX2 | 12q24.33 |
| P2X3 P2RX3 P2X purinoceptor 3 is a protein that in humans is encoded by the P2RX3 gene.... |
P2RX3 | 11q12 |
| P2X4 P2RX4 P2X purinoceptor 4 is a protein that in humans is encoded by the P2RX4 gene.... |
P2RX4 | 12q24.32 |
| P2X5 P2RX5 P2X purinoceptor 5 is a protein that in humans is encoded by the P2RX5 gene.... |
P2RX5 | 17p13.3 |
| P2X6 P2RX6 P2X purinoceptor 6 is a protein that in humans is encoded by the P2RX6 gene.... |
P2RX6 | 22p11.21 |
| P2X7 P2RX7 P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.-Recruitment of pannexin:Activation of the P2RX7 receptor by ATP leads to recruitment of pannexin pores which allow small molecules such as ATP to leak out of cells. This allows further activation of purinergic receptors... |
P2RX7 | 12q24 |
The subunits all share a common topology, possessing two plasma membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
spanning domains, a large extracellular loop and intracellular carboxyl
C-terminal end
The C-terminus is the end of an amino acid chain , terminated by a free carboxyl group . When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus...
and amino
N-terminal end
The N-terminus refers to the start of a protein or polypeptide terminated by an amino acid with a free amine group . The convention for writing peptide sequences is to put the N-terminus on the left and write the sequence from N- to C-terminus...
termini (Figure 1). With the exception of P2X6, each subunit can readily form a functional homomeric
Homomeric
A homomeric substance is one which is made out of any number of identical products or molecules.e.g. A homomeric peptide = glutathione A peptide which is made up of only a single type of amino acid subunit; e.g., alanylalanylalanine.ALA-ALA-ALA...
receptor . 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 when expressed alone, but nevertheless can co-assemble with other subunits to form functional heteromeric receptors. Current data suggests that, all of the P2X subunits are capable of forming heteromeric P2X receptors with at least one other subunit type.
Evidence from early molecular biological and functional studies has strongly indicated that the functional P2X receptor protein is a trimer
Trimer (biochemistry)
In biochemistry, a trimer is a macromolecular complex formed by three, usually non-covalently bound, macromolecules like proteins or nucleic acids. A homo-trimer would be formed by three identical molecules. A hetero-trimer would be formed by three different macromolecules. Collagen is an example...
, with the three peptide subunits
Protein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...
arranged around an ion-permeable channel pore. This view was recently confirmed by the use of X-ray crystallography
X-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
to resolve the three-dimensional structure of the zebrafish P2X4 receptor (Figure 2).
The relationship between the structure and function of P2X receptors has been the subject of considerable research, and key protein domains responsible for regulating ATP binding, ion permeation, pore dilation and desensitization have been identified.
Pharmacology
The pharmacology of a given P2X receptor is largely determined by its subunit makeup. 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'-disulphonic acid (PPADSPPADS
PPADS is a selective purinergic P2X antagonist. It is able to block contractions of rabbit vas deferens induced by ATP or α,β,methylene-ATP. It appears to be relatively selection for P2X receptors, having no appreciable activity at α1 adrenergic, muscarinic M2 and M3, histamine H1, and adenosine...
) and suramin
Suramin
Suramin is a drug developed by Oskar Dressel and Richard Kothe of Bayer, Germany in 1916, and is still sold by Bayer under the brand name Germanin.According to the National Cancer Institute there are no active clinical trials...
. 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
Propidium iodide
Propidium iodide is an intercalating agent and a fluorescent molecule with a molecular mass of 668.4 Da that can be used to stain cells. When excited with 488 nm wavelength light, it fluoresces red...
(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.
Tissue distribution
P2X receptors are expressed in cells from a wide variety of animal tissuesBiological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
. On presynaptic and postsynaptic nerve terminals
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
throughout the central
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, peripheral
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
and autonomic
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
nervous systems, P2X receptors have been shown to modulate synaptic transmission
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
. Furthermore, P2X receptors are able to initiate contraction
Muscle contraction
Muscle fiber generates tension through the action of actin and myosin cross-bridge cycling. While under tension, the muscle may lengthen, shorten, or remain the same...
in cells of the heart muscle, skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
, and various smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
tissues, including that of the vasculature
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
, vas deferens
Vas deferens
The vas deferens , also called ductus deferens, , is part of the male anatomy of many vertebrates; they transport sperm from the epididymis in anticipation of ejaculation....
and urinary bladder
Urinary bladder
The urinary bladder is the organ that collects urine excreted by the kidneys before disposal by urination. A hollow muscular, and distensible organ, the bladder sits on the pelvic floor...
. P2X receptors are also expressed on leukocytes
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
, including lymphocytes and macrophages, and are present on blood platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s. 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 neuron
Sensory neuron
Sensory neurons are typically classified as the neurons responsible for converting external stimuli from the environment into internal stimuli. They are activated by sensory input , and send projections into the central nervous system that convey sensory information to the brain or spinal cord...
s, where they often co-assemble into functional P2X2/3 receptors.
Physiological roles
In keeping with their wide distribution throughout the body, P2X receptors are involved in a variety of physiological processes, including:- Modulation of cardiac rhythm and contractilityContractilityMyocardial contractility is the intrinsic ability of the heart to contract independent of preload and afterload. Changes in the ability to produce force during contraction result from different degrees of binding between myosin and actin filaments...
- Modulation of vascular toneVascular resistanceVascular resistance is a term used to define the resistance to flow that must be overcome to push blood through the circulatory system. The resistance offered by the peripheral circulation is known as the systemic vascular resistance , while the resistance offered by the vasculature of the lungs...
- Mediation of nociception - e.g. hypersensitivity to innocuous stimuli following upregulation of P2X4 in the spinal cord
- Contraction of the vas deferensVas deferensThe vas deferens , also called ductus deferens, , is part of the male anatomy of many vertebrates; they transport sperm from the epididymis in anticipation of ejaculation....
during ejaculationEjaculationEjaculation is the ejecting of semen from the male reproductory tract, and is usually accompanied by orgasm. It is usually the final stage and natural objective of male sexual stimulation, and an essential component of natural conception. In rare cases ejaculation occurs because of prostatic disease...
Activation and channel opening
ATP binds to the extracellular loop of the P2X receptor, whereupon it evokes a conformational changeConformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
in the structure of the ion channel that results in the opening of the ion-permeable pore. This allows cations such as Na+
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
and Ca2+
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
to enter the cell, leading to depolarization
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
of the cell membrane and the activation of various Ca2+-sensitive intracellular processes. The channel opening time is dependent upon the subunit makeup of the receptor. For example, P2X1 and P2X3 receptors desensitize
Desensitization
Desensitization can refer to:* Desensitization * Desensitization * Desensitization * Desensitization of explosives, see Phlegmatized...
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. 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. The precise mechanism by which the binding of ATP leads to the opening of the P2X receptor channel pore is not well understood, but is currently under investigation.
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. In contrast to the other members of the P2X receptor family, P2X4 receptors are also very sensitive to modulation by the macrocyclic lactone, ivermectin. 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.Subfamilies
- P2RX1P2RX1P2X purinoceptor 1 is a protein that in humans is encoded by the P2RX1 gene....
- P2RX2P2RX2P2X purinoceptor 2 is a protein that in humans is encoded by the P2RX2 gene....
- P2RX3P2RX3P2X purinoceptor 3 is a protein that in humans is encoded by the P2RX3 gene....
- P2RX4P2RX4P2X purinoceptor 4 is a protein that in humans is encoded by the P2RX4 gene....
- P2RX5P2RX5P2X purinoceptor 5 is a protein that in humans is encoded by the P2RX5 gene....
- P2RX6P2RX6P2X purinoceptor 6 is a protein that in humans is encoded by the P2RX6 gene....
- P2RX7P2RX7P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.-Recruitment of pannexin:Activation of the P2RX7 receptor by ATP leads to recruitment of pannexin pores which allow small molecules such as ATP to leak out of cells. This allows further activation of purinergic receptors...
Human proteins containing this domain
P2RX1P2RX1
P2X purinoceptor 1 is a protein that in humans is encoded by the P2RX1 gene....
; P2RX2
P2RX2
P2X purinoceptor 2 is a protein that in humans is encoded by the P2RX2 gene....
; P2RX3
P2RX3
P2X purinoceptor 3 is a protein that in humans is encoded by the P2RX3 gene....
; P2RX4
P2RX4
P2X purinoceptor 4 is a protein that in humans is encoded by the P2RX4 gene....
; P2RX5
P2RX5
P2X purinoceptor 5 is a protein that in humans is encoded by the P2RX5 gene....
; P2RX7
P2RX7
P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.-Recruitment of pannexin:Activation of the P2RX7 receptor by ATP leads to recruitment of pannexin pores which allow small molecules such as ATP to leak out of cells. This allows further activation of purinergic receptors...
; P2RXL1; TAX1BP3
TAX1BP3
Tax1-binding protein 3 is a protein that in humans is encoded by the TAX1BP3 gene. This name is in reference to the Tax1 protein of the Human T-cell Lymphotropic Virus which was used to discover Tax1BP3 in a yeast 2-hybrid screen and subsequently verified by co-IP. TIP1, as it is also known, is a...