P2X purinoceptor 4 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''P2RX4''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
The product of this gene belongs to the family of
purinoceptors for
ATP. Multiple
alternatively spliced
Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be in ...
transcript variants have been identified for this gene although their full-length natures have not been determined.
The receptor is found in the central and peripheral nervous systems, in the epithelia of ducted glands and airways, in the smooth muscle of the
bladder
The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters ...
,
gastrointestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...
,
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
, and
arteries
An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pul ...
, in uterine
endometrium
The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional laye ...
, and in
fat cells
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
. P2X
4 receptors have been implicated in the regulation of cardiac function, ATP-mediated
cell death
Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...
,
synaptic strengthening, and activating of the
inflammasome
Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-in ...
in response to injury.
Receptor structure and kinetics
The P2X
4 subunits can form
homomeric
Something that is composed of one repeating subunit, the antonym of heteromeric. It is often used to describe proteins made up of multiple identical repeating polypeptide chains e.g. beta galactosidase
β-Galactosidase (EC 3.2.1.23, lactase, ...
or
heteromeric A heteromer is something that consists of different parts; the antonym of homomeric. Examples are:
Biology
* Spinal neurons that pass over to the opposite side of the spinal cord.
* A protein complex that contains two or more different polypeptide ...
receptors. The P2X
4 receptor has a typical
P2X receptor
The ATP-gated P2X receptor cation channel familyTC# 1.A.7, or simply P2X receptor family, consists of cation-permeable ligand-gated ion channels that open in response to the binding of extracellular adenosine 5'-triphosphate ( ATP). They belong ...
structure. The
zebrafish
The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family ( Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...
P2X
4 receptor was the first purinergic receptor to be crystallized and have its three-dimensional structure solved, forming the model for the P2X receptor family.
The P2X
4 receptor is a
ligand-gated cation channel that opens in response to ATP binding.
The P2X
4 receptor has high
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
permeability, leading to the
depolarization
In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...
of the cell membrane and the activation of various Ca
2+-sensitive intracellular processes.
Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG
+) in about 50% of the cells expressing the P2X
4 receptor.
The
desensitization of P2X
4 receptors is intermediate when compared to
P2X1 and
P2X2 receptors.
Pharmacology
Agonists
P2X
4 receptors respond to ATP, but not αβmeATP. These receptors are also potentiated by
ivermectin
Ivermectin (, '' EYE-vər-MEK-tin'') is an antiparasitic drug. After its discovery in 1975, its first uses were in veterinary medicine to prevent and treat heartworm and acariasis. Approved for human use in 1987, today it is used to treat inf ...
, cibacron blue, and
zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
.
Antagonists
The main pharmacological distinction between the members of the
purinoceptor family is the relative sensitivity to the antagonists
suramin
Suramin is a medication used to treat African sleeping sickness and river blindness. It is the treatment of choice for sleeping sickness without central nervous system involvement. It is given by injection into a vein.
Suramin causes a fair n ...
and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (
PPADS). The product of this gene has the lowest sensitivity for these antagonists
Receptor trafficking
P2X
4 receptors are stored in
lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...
s and brought to the cell surface in response to extracellular signals. These signals include
IFN-γ
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
,
CCL21
Chemokine (C-C motif) ligand 21 (CCL21) is a small cytokine belonging to the CC chemokine family. This chemokine is also known as 6Ckine (because it has six conserved cysteine residues instead of the four cysteines typical to chemokines), exodus- ...
,
CCL2
''For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.''
The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL ...
.
Fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
is also involved in upregulation of P2X
4 receptors through interactions with
integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
s that lead to the activation of
SRC-family kinase
Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily. Frk has homologs i ...
member,
Lyn. Lyn then activates
PI3K-AKT and
MEK-ERK signaling pathways to stimulate receptor trafficking. Internalization of P2X
4 receptors is
clathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. Whe ...
- and
dynamin
Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamin is part of the "dynamin superfamily", which includes classical dynamins, dynamin-like proteins, Mx proteins, OPA1, mitofusins, and GBPs. Members of the dynamin fa ...
-dependent
endocytosis
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
.
Neuropathic pain
The P2X
4 receptor has been linked to
neuropathic pain
Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous ...
mediated by
microglia
Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...
''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' and ''
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
''. P2X
4 receptors are upregulated following injury. This upregulation allows for increased activation of
p38 mitogen-activated protein kinases
p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differe ...
, thereby increasing the release of brain-derived neurotrophic factor (
BDNF
Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...
) from microglia. BDNF released from microglia induces neuronal hyperexcitability through interaction with the
TrkB receptor
Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the ''NTRK2'' gene. TrkB is a recepto ...
. More importantly, recent work shows that P2X
4 receptor activation is not only necessary for neuropathic pain, but it is also sufficient to cause neuropathic pain.
See also
*
P2X receptor
The ATP-gated P2X receptor cation channel familyTC# 1.A.7, or simply P2X receptor family, consists of cation-permeable ligand-gated ion channels that open in response to the binding of extracellular adenosine 5'-triphosphate ( ATP). They belong ...
References
Further reading
*
*
*
*
*
*
*
*
*
*
*
*
*
External links
*
{{Purinergics
Ion channels