P2RX7

Last updated
P2RX7
Identifiers
Aliases P2RX7 , P2X7, purinergic receptor P2X 7
External IDs OMIM: 602566; MGI: 1339957; HomoloGene: 1925; GeneCards: P2RX7; OMA:P2RX7 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5027

18439

Ensembl

ENSG00000089041

ENSMUSG00000029468

UniProt

Q99572

Q9Z1M0

RefSeq (mRNA)

NM_002562
NM_177427

NM_001038839
NM_001038845
NM_001038887
NM_001284402
NM_011027

Contents

RefSeq (protein)

NP_002553

NP_001033928
NP_001033934
NP_001033976
NP_001271331
NP_035157

Location (UCSC) Chr 12: 121.13 – 121.19 Mb Chr 5: 122.78 – 122.83 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene. [5] [6]

The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced variants which would encode different isoforms have been identified although some fit nonsense-mediated decay criteria. [7]

The receptor is found in the central and peripheral nervous systems, in microglia, in macrophages, in uterine endometrium, and in the retina. [8] [9] [10] [11] [12] [13] [14] The P2X7 receptor also serves as a pattern recognition receptor for extracellular ATP-mediated apoptotic cell death, [15] [16] [17] regulation of receptor trafficking, [18] mast cell degranulation, [19] [20] and inflammation. [21] [19] [20] [22] Regarding inflammation, P2X7 receptor induces the NLRP3 inflammasome in myeloid cells and leads to interleukin-1beta release. [23]

Structure and kinetics

The P2X7 subunits can form homomeric receptors only with a typical P2X receptor structure. [24] The P2X7 receptor is a ligand-gated cation channel that opens in response to ATP binding and leads to cell depolarization. The P2X7 receptor requires higher levels of ATP than other P2X receptors; however, the response can be potentiated by reducing the concentration of divalent cations such as calcium or magnesium. [8] [25] Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG+). [25] P2X7 receptors do not become desensitized readily and continued signaling leads to the aforementioned increased permeability and an increase in current amplitude. [25]

Pharmacology

Agonists

Antagonists

Receptor trafficking

In microglia, P2X7 receptors are found mostly on the cell surface. [28] Conserved cysteine residues located in the carboxyl terminus seem to be important for receptor trafficking to the cell membrane. [29] These receptors are upregulated in response to peripheral nerve injury. [30]

In melanocytic cells P2X7 gene expression may be regulated by MITF. [31]

Recruitment of pannexin

Activation of the P2X7 receptor by ATP leads to recruitment of pannexin pores [32] which allow small molecules such as ATP to leak out of cells. This allows further activation of purinergic receptors and physiological responses such a spreading cytoplasmic waves of calcium. [33] Moreover, this could be responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to larger molecules.

Clinical significance

Inflammation

On T cells activation of P2X7 receptors can activate the T cells or cause T cell differentiation, can affect T cell migration or (at high extracellular levels of ATP and/or NAD+) can induce cell death. [34] The CD38 enzyme on B lymphocytes and macrophages reduces extracellular NAD+, promoting the survival of T cells. [35]

Neuropathic pain

Microglial P2X7 receptors are thought to be involved in neuropathic pain because blockade or deletion of P2X7 receptors results in decreased responses to pain, as demonstrated in vivo . [36] [37] Moreover, P2X7 receptor signaling increases the release of proinflammatory molecules such as IL-1β, IL-6, and TNF-α. [38] [39] [40] In addition, P2X7 receptors have been linked to increases in proinflammatory cytokines such as CXCL2 and CCL3. [41] [42] P2X7 receptors are also linked to P2X4 receptors, which are also associated with neuropathic pain mediated by microglia. [28]

Osteoporosis

Mutations in this gene have been associated to low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women. [43]

Diabetes

The ATP/P2X7R pathway may trigger T-cell attacks on the pancreas, rendering it unable to produce insulin. This autoimmune response may be an early mechanism by which the onset of diabetes is caused. [44] [45]

Research

One study in mice showed that blockade of P2X7 receptors attenuates onset of liver fibrosis. [46]

See also

Related Research Articles

<span class="mw-page-title-main">Microglia</span> Glial cell located throughout the brain and spinal cord

Microglia are a type of neuroglia located throughout the brain and spinal cord. Microglia account for about 10-15% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS). Microglia originate in the yolk sac under a tightly regulated molecular process. These cells are distributed in large non-overlapping regions throughout the CNS. Microglia are key cells in overall brain maintenance—they are constantly scavenging the CNS for plaques, damaged or unnecessary neurons and synapses, and infectious agents. Since these processes must be efficient to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. This sensitivity is achieved in part by the presence of unique potassium channels that respond to even small changes in extracellular potassium. Recent evidence shows that microglia are also key players in the sustainment of normal brain functions under healthy conditions. Microglia also constantly monitor neuronal functions through direct somatic contacts and exert neuroprotective effects when needed.

P2Y<sub>12</sub> Protein-coding gene in the species Homo sapiens

P2Y12 is a chemoreceptor for adenosine diphosphate (ADP) that belongs to the Gi class of a group of G protein-coupled (GPCR) purinergic receptors. This P2Y receptor family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. The P2Y12 receptor is involved in platelet aggregation and is thus a biological target for the treatment of thromboembolisms and other clotting disorders. Two transcript variants encoding the same isoform have been identified for this gene.

<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">P2X purinoreceptor</span>

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). They belong to a larger family of receptors known as the ENaC/P2X superfamily. ENaC and P2X receptors have similar 3-D structures and are homologous. P2X receptors are present in a diverse array of organisms including humans, mouse, rat, rabbit, chicken, zebrafish, bullfrog, fluke, and amoeba.

<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.

Gliotransmitters are chemicals released from glial cells that facilitate neuronal communication between neurons and other glial cells. They are usually induced from Ca2+ signaling, although recent research has questioned the role of Ca2+ in gliotransmitters and may require a revision of the relevance of gliotransmitters in neuronal signalling in general.

<span class="mw-page-title-main">P2RY1</span> Protein-coding gene in the species Homo sapiens

P2Y purinoceptor 1 is a protein that in humans is encoded by the P2RY1 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">P2RY2</span> Protein-coding gene in the species Homo sapiens

P2Y purinoceptor 2 is a protein that in humans is encoded by the P2RY2 gene.

<span class="mw-page-title-main">ENTPD1</span> Mammalian protein found in humans

Ectonucleoside triphosphate diphosphohydrolase-1 also known as CD39, is a typical cell surface enzyme with a catalytic site on the extracellular face.

<span class="mw-page-title-main">P2RY11</span> Protein-coding gene in the species Homo sapiens

P2Y purinoceptor 11 is a protein that in humans is encoded by the P2RY11 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">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.

Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger signals, and alarmins because they serve as warning signs to alert the organism to any damage or infection to its cells. DAMPs are endogenous danger signals that are discharged to the extracellular space in response to damage to the cell from mechanical trauma or a pathogen. Once a DAMP is released from the cell, it promotes a noninfectious inflammatory response by binding to a pattern recognition receptor (PRR). Inflammation is a key aspect of the innate immune response; it is used to help mitigate future damage to the organism by removing harmful invaders from the affected area and start the healing process. As an example, the cytokine IL-1α is a DAMP that originates within the nucleus of the cell which, once released to the extracellular space, binds to the PRR IL-1R, which in turn initiates an inflammatory response to the trauma or pathogen that initiated the release of IL-1α. In contrast to the noninfectious inflammatory response produced by DAMPs, pathogen-associated molecular patterns (PAMPs) initiate and perpetuate the infectious pathogen-induced inflammatory response. Many DAMPs are nuclear or cytosolic proteins with defined intracellular function that are released outside the cell following tissue injury. This displacement from the intracellular space to the extracellular space moves the DAMPs from a reducing to an oxidizing environment, causing their functional denaturation, resulting in their loss of function. Outside of the aforementioned nuclear and cytosolic DAMPs, there are other DAMPs originated from different sources, such as mitochondria, granules, the extracellular matrix, the endoplasmic reticulum, and the plasma membrane.

<span class="mw-page-title-main">Rostral ventromedial medulla</span> Group of neurons in medulla of brain

The rostral ventromedial medulla (RVM), or ventromedial nucleus of the spinal cord, is a group of neurons located close to the midline on the floor of the medulla oblongata. The rostral ventromedial medulla sends descending inhibitory and excitatory fibers to the dorsal horn spinal cord neurons. There are 3 categories of neurons in the RVM: on-cells, off-cells, and neutral cells. They are characterized by their response to nociceptive input. Off-cells show a transitory decrease in firing rate right before a nociceptive reflex, and are theorized to be inhibitory. Activation of off-cells, either by morphine or by any other means, results in antinociception. On-cells show a burst of activity immediately preceding nociceptive input, and are theorized to be contributing to the excitatory drive. Neutral cells show no response to nociceptive input.

<span class="mw-page-title-main">Purinergic signalling</span> Signalling complex involving purine nucleosides and their receptors

Purinergic signalling is a form of extracellular signalling mediated by purine nucleotides and nucleosides such as adenosine and ATP. It involves the activation of purinergic receptors in the cell and/or in nearby cells, thereby regulating cellular functions.

The prostaglandin D2 (PGD2) receptors are G protein-coupled receptors that bind and are activated by prostaglandin D2. Also known as PTGDR or DP receptors, they are important for various functions of the nervous system and inflammation. They include the following proteins:

Microglia are the primary immune cells of the central nervous system, similar to peripheral macrophages. They respond to pathogens and injury by changing morphology and migrating to the site of infection/injury, where they destroy pathogens and remove damaged cells.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029468 – Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  7. ↑ "Entrez Gene: P2RX7 purinergic receptor P2X, ligand-gated ion channel, 7".
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  39. ↑ Shigemoto-Mogami Y, Koizumi S, Tsuda M, Ohsawa K, Kohsaka S, Inoue K (September 2001). "Mechanisms underlying extracellular ATP-evoked interleukin-6 release in mouse microglial cell line, MG-5". Journal of Neurochemistry. 78 (6): 1339–49. doi: 10.1046/j.1471-4159.2001.00514.x . PMID   11579142. S2CID   44660159.
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  42. ↑ Kataoka A, Tozaki-Saitoh H, Koga Y, Tsuda M, Inoue K (January 2009). "Activation of P2X7 receptors induces CCL3 production in microglial cells through transcription factor NFAT". Journal of Neurochemistry. 108 (1): 115–25. doi: 10.1111/j.1471-4159.2008.05744.x . PMID   19014371. S2CID   205619872.
  43. ↑ Gartland A, Skarratt KK, Hocking LJ, Parsons C, Stokes L, Jørgensen NR, et al. (May 2012). "Polymorphisms in the P2X7 receptor gene are associated with low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women". European Journal of Human Genetics. 20 (5): 559–64. doi:10.1038/ejhg.2011.245. PMC   3330223 . PMID   22234152.
  44. ↑ "Silencing immune attacks in type 1 diabetes". June 10, 2013. Retrieved June 15, 2013.
  45. ↑ "Boston Children's Hospital Finds Root Cause of Diabetes". June 13, 2013. Retrieved June 15, 2013.
  46. ↑ Huang C, Yu W, Cui H, Wang Y, Zhang L, Han F, Huang T (January 2014). "P2X7 blockade attenuates mouse liver fibrosis". Molecular Medicine Reports. 9 (1): 57–62. doi: 10.3892/mmr.2013.1807 . PMID   24247209.

Further reading

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