Download Gene Section P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7)

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
P2RX7 (purinergic receptor P2X, ligand-gated ion
channel, 7)
Pablo Pelegrin, Annmarie Surprenant
Faculty of Life Science, Michael Smith Building, University of Manchester, Manchester, M13 9PT, UK
Published in Atlas Database: January 2008
Online updated version: http://AtlasGeneticsOncology.org/Genes/P2RX7ID41623ch12q24.html
DOI: 10.4267/2042/38574
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
cells (mainly in antigen presenting cells, such as
monocytes, macrophages and dendritic cells).
Hugo: P2RX7
Other names: MGC20089; P2X7; P2Z
Location: 12q24.31
Localisation
Mainly is found in the plasma membrane, however it
also can be found in intracellular membrane
compartments while trafficking to the plasma
membrane.
DNA/RNA
Description
Function
The P2RX7 gene is comprised of 13 coding exons.
Acts as a ligand gated ion channel, sensing high
concentration of extracellular ATP. Responsible for
ATP-dependent
activation
and
release
of
proinflammatory cytokines of the interleukin-1 family,
mainly
interleukin-1beta,
interleukin-18
and
interleukin-1alpha, playing a pivotal role in
inflammatory responses. Prolonged stimulation of the
P2X7 receptor can lead to plasma membrane bleb
formation, opening of pannexin-1 dependent membrane
pores and eventual cell death.
Transcription
The full length transcript is 3135 bp long and 10
alternative splicing isoforms have been identified.
Pseudogene
Not known.
Protein
Description
Homology
The protein has 595 residues amino acids and
compromises a 69 kDa calculated molecular weight.
However, N-glycosylation in the extracellular loop
increases the size of the P2X7 receptor to about 75-85
kDa; the protein is composed successively (from the Nto the C-terminus) by:
- 25 amino acid intracellular N-terminus
- 21 amino acid first transmembrane domain
- 288 amino acid extracellular loop
- 21 amino acid second transmembrane domain
- 240 amino acid intracellular C-terminal region
With other P2X receptors, with the higher homology
with P2RX4. Excluding the unique C-terminal domain,
homology is 39-49% with other P2X receptors.
Mutations
Germinal
The human P2X7 receptor gene is highly polymorphic
and more then 260 SNP have been described, only four
loss-of-function and one gain-of-function SNP have
been described to date:
- Loss of protein function:
946 G to A (Arg-307 to Gln)
1068 G to A (Ala-348 to Thr)
1513 A to C (Glu-496 to Ala)
1729 T to A (Ile-568 to Asp)
Expression
In a wide variety of tissues including heart, liver,
pancreas, thymus, skeletal muscle and brain, although
in brain the expression is mainly restricted to microglia.
It also has relevant expression and function in immune
Atlas Genet Cytogenet Oncol Haematol. 2008;12(5)
377
P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7)
Pelegrin P, Surprenant A
Dao-Ung LP, Fuller SJ, Sluyter R, SkarRatt KK, Thunberg U,
Tobin G, Byth K, Ban M, Rosenquist R, Stewart GJ, Wiley JS.
Association of the 1513C polymorphism in the P2X7 gene with
familial forms of chronic lymphocytic leukaemia. Br J Haematol
2004;125:815-817.
- Gain of protein function:
489 C to T (His-155 to Tyr)
Somatic
Not known in human.
Gu BJ, Sluyter R, Skarratt KK, Shemon AN, Dao-Ung LP,
Fuller SJ, Barden JA, Clarke AL, Petrou S, Wiley JS. An
Arg307 to Gln polymorphism within the ATP-binding site
causes loss of function of the human P2X7 receptor. J Biol
Chem 2004;279:31287-31295.
Implicated in
Extrapulmonary tuberculosis
Slater M, Danieletto S, Pooley M, Cheng Teh L, Gidley-Baird
A, Barden JA. Differentiation between cancerous and normal
hyperplastic lobules in breast lesions. Breast Cancer Res Treat
2004;83:1-10.
Note: The P2RX7 1513C allele has been strongly
associated with extrapulmonary tuberculosis. The allele
was associated with a reduced killing of
Mycobacterium tuberculosis by macrophages.
Slater M, Danieletto S, Gidley-Baird A, Teh LC, Barden JA.
Early prostate cancer detected using expression of nonfunctional
cytolytic
P2X7
receptors.
Histopathology
2004;44:206-215.
Chronic lymphoid leukemia (CLL)
Note: The 1513C allele of P2RX7 has been associated
with the clinical course of patients affected by chronic
lymphocytic leukemia (CLL).
There is a possible role for the P2X7 receptor in the
susceptibility to familial CLL or, alternately, the 1513C
allele may be in linkage disequilibrium with a nearby
susceptibility gene.
Adinolfi E, Callegari MG, Ferrari D, Bolognesi C, Minelli M,
Wieckowski MR, Pinton P, Rizzuto R, Di Virgilio F. Basal
activation of the P2X7 ATP receptor elevates mitochondrial
calcium and potential, increases cellular ATP levels, and
promotes serum-independent growth. Mol Biol Cell
2005;16:3260-3272.
Cabrini G, Falzoni S, Forchap SL, Pellegatti P, Balboni A,
Agostini P, Cuneo A, Castoldi G, Baricordi OR, Di Virgilio F. A
His-155 to Tyr polymorphism confers gain-of-function to the
human P2X7 receptor of human leukemic lymphocytes. J
Immunol 2005;175:82-89.
Various cancers, including breast
cancer, prostate cancer, papillary
thyroid cancer and neuroblastoma
Cheewatrakoolpong B, Gilchrest H, Anthes JC, Greenfeder S.
Identification and characterization of splice variants of the
human P2X7 ATP channel. Biochem Biophys Res Commun
2005;332:17-27.
Note: P2X7 receptor is overexpressed in a variety of
cancers (see above). A detailed understanding of the
mechanistic contribution mediated by P2RX7 has yet to
be established. However, there is substantial evidence
that the P2X7 receptor may mediate cell survival and
growth by increasing the efficiency of oxidative
phosphorylation and total intracellular ATP stores.
Finally it has been proposed that the P2X7 receptor
may be a candidate marker of papillary thyroid cancer.
Feng YH, Li X, Wang L, Zhou L, Gorodeski GI. A truncated
P2X7 receptor variant (P2X7-j) endogenously expressed in
cervical cancer cells antagonizes the full-length P2X7 receptor
through hetero-oligomerization. J Biol Chem 2006;281:1722817237.
Ferrari D, Pizzirani C, Adinolfi E, Lemoli RM, Curti A, Idzko M,
Panther E, Di Virgilio F. The P2X7 receptor: a key player in IL1 processing and release. J Immunol 2006;176:3877-3883.
(Review).
References
Pelegrin P, Surprenant A. Pannexin-1 mediates large pore
formation and interleukin-1beta release by the ATP-gated
P2X7 receptor. EMBO J 2006;25:5071-5082.
Surprenant A, Rassendren F, Kawashima E, North RA, Buell
G. The cytolytic P2Z receptor for extracellular ATP identified as
a P2X receptor (P2X7). Science 1996;272:735-738.
Raffaghello L, Chiozzi P, Falzoni S, Di Virgilio F, Pistoia V. The
P2X7 receptor sustains the growth of human neuroblastoma
cells through a substance P-dependent mechanism. Cancer
Res 2006;66:907-914.
Rassendren F, Buell GN, Virginio C, Collo G, North RA,
Surprenant A. The permeabilizing ATP receptor, P2X7.
Cloning and expression of a human cDNA. J Biol Chem
1997;272:5482-5486.
Fernando SL, Saunders BM, Sluyter R, Skarratt KK, Goldberg
H, Marks GB, Wiley JS, Britton WJ. A polymorphism in the
P2X7 gene increases susceptibility to extrapulmonary
tuberculosis. Am J Respir Crit Care Med 2007;175:360-366.
Gu BJ, Zhang W, Worthington RA, Sluyter R, Dao-Ung P,
Petrou S, Barden JA, Wiley JS. A Glu-496 to Ala polymorphism
leads to loss of function of the human P2X7 receptor. J Biol
Chem 2001;276:11135-11142.
Solini A, Cuccato S, Ferrari D, Santini E, Gulinelli S, Callegari
MG, Dardano A, Faviana P, Madec S, Di Virgilio F, Monzani F.
Increased P2X7 Receptor Expression and Function in Thyroid
Papillary Cancer: A New Potential Marker of the Disease?.
Endocrinology 2008;149:389-396.
Adinolfi E, Melchiorri L, Falzoni S, Chiozzi P, Morelli A, Tieghi
A, Cuneo A, Castoldi G, Di Virgilio F, Baricordi OR. P2X7
receptor expression in evolutive and indolent forms of chronic
B lymphocytic leukemia. Blood 2002;99:706-708.
North RA. Molecular physiology of P2X receptors. Physiol Rev
2002;82:1013-1067. (Review).
This article should be referenced as such:
Pelegrin P, Surprenant A. P2RX7 (purinergic receptor P2X,
ligand-gated ion channel, 7). Atlas Genet Cytogenet Oncol
Haematol.2008;12(5):377-378.
Wiley JS, Dao-Ung LP, Li C, Shemon AN, Gu BJ, Smart ML,
Fuller SJ, Barden JA, Petrou S, Sluyter R. An Ile-568 to Asn
polymorphism prevents normal trafficking and function of the
human P2X7 receptor. J Biol Chem 2003;278:17108-17113.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(5)
378