Alternatively Spliced Isoforms of the P2X7 Receptor: Structure, Function and Disease Associations

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Jul 28

PMID 35897750

Authors

Sophie K F De Salis

Lanxin Li

Zheng Chen

Kam Wa Lam

Kristen K Skarratt

Thomas Balle

Stephen J Fuller

Affiliations

Soon will be listed here.

Abstract

The P2X7 receptor (P2X7R) is an ATP-gated membrane ion channel that is expressed by multiple cell types. Following activation by extracellular ATP, the P2X7R mediates a broad range of cellular responses including cytokine and chemokine release, cell survival and differentiation, the activation of transcription factors, and apoptosis. The P2X7R is made up of three P2X7 subunits that contain specific domains essential for the receptor's varied functions. Alternative splicing produces P2X7 isoforms that exclude one or more of these domains and assemble in combinations that alter P2X7R function. The modification of the structure and function of the P2X7R may adversely affect cellular responses to carcinogens and pathogens, and alternatively spliced (AS) P2X7 isoforms have been associated with several cancers. This review summarizes recent advances in understanding the structure and function of AS P2X7 isoforms and their associations with cancer and potential role in modulating the inflammatory response.

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References

Bin Dayel A, Evans R, Schmid R . Mapping the Site of Action of Human P2X7 Receptor Antagonists AZ11645373, Brilliant Blue G, KN-62, Calmidazolium, and ZINC58368839 to the Intersubunit Allosteric Pocket. Mol Pharmacol. 2019; 96(3):355-363. PMC: 6701605. DOI: 10.1124/mol.119.116715. View

Benzaquen J, Janho Dit Hreich S, Heeke S, Juhel T, Lalvee S, Bauwens S . P2RX7B is a new theranostic marker for lung adenocarcinoma patients. Theranostics. 2020; 10(24):10849-10860. PMC: 7532666. DOI: 10.7150/thno.48229. View

Allsopp R, Dayl S, Bin Dayel A, Schmid R, Evans R . Mapping the Allosteric Action of Antagonists A740003 and A438079 Reveals a Role for the Left Flipper in Ligand Sensitivity at P2X7 Receptors. Mol Pharmacol. 2018; 93(5):553-562. PMC: 5896373. DOI: 10.1124/mol.117.111021. View

Nicke A, Kuan Y, Masin M, Rettinger J, Marquez-Klaka B, Bender O . A functional P2X7 splice variant with an alternative transmembrane domain 1 escapes gene inactivation in P2X7 knock-out mice. J Biol Chem. 2009; 284(38):25813-22. PMC: 2757983. DOI: 10.1074/jbc.M109.033134. View

Buell G, Talabot F, Gos A, Lorenz J, Lai E, Morris M . Gene structure and chromosomal localization of the human P2X7 receptor. Recept Channels. 1998; 5(6):347-54. View

Riedel T, Schmalzing G, Markwardt F . Influence of extracellular monovalent cations on pore and gating properties of P2X7 receptor-operated single-channel currents. Biophys J. 2007; 93(3):846-58. PMC: 1913143. DOI: 10.1529/biophysj.106.103614. View

Worthley D, Churchill M, Compton J, Tailor Y, Rao M, Si Y . Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell. 2015; 160(1-2):269-84. PMC: 4436082. DOI: 10.1016/j.cell.2014.11.042. View

Pan Q, Shai O, Lee L, Frey B, Blencowe B . Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008; 40(12):1413-5. DOI: 10.1038/ng.259. View

Boldrini L, Giordano M, Ali G, Servadio A, Pelliccioni S, Niccoli C . P2X7 protein expression and polymorphism in non-small cell lung cancer (NSCLC). J Negat Results Biomed. 2014; 13:16. PMC: 4158335. DOI: 10.1186/1477-5751-13-16. View

10.

Jorgensen N, Henriksen Z, Sorensen O, Eriksen E, Civitelli R, Steinberg T . Intercellular calcium signaling occurs between human osteoblasts and osteoclasts and requires activation of osteoclast P2X7 receptors. J Biol Chem. 2002; 277(9):7574-80. DOI: 10.1074/jbc.M104608200. View

11.

Cheewatrakoolpong B, Gilchrest H, Anthes J, Greenfeder S . Identification and characterization of splice variants of the human P2X7 ATP channel. Biochem Biophys Res Commun. 2005; 332(1):17-27. DOI: 10.1016/j.bbrc.2005.04.087. View

12.

Rassendren F, Buell G, Virginio C, Collo G, North R, Surprenant A . The permeabilizing ATP receptor, P2X7. Cloning and expression of a human cDNA. J Biol Chem. 1997; 272(9):5482-6. DOI: 10.1074/jbc.272.9.5482. View

13.

Baralle F, Giudice J . Alternative splicing as a regulator of development and tissue identity. Nat Rev Mol Cell Biol. 2017; 18(7):437-451. PMC: 6839889. DOI: 10.1038/nrm.2017.27. View

14.

Furlanis E, Scheiffele P . Regulation of Neuronal Differentiation, Function, and Plasticity by Alternative Splicing. Annu Rev Cell Dev Biol. 2018; 34:451-469. PMC: 6697533. DOI: 10.1146/annurev-cellbio-100617-062826. View

15.

Wiley J, Sluyter R, Gu B, Stokes L, Fuller S . The human P2X7 receptor and its role in innate immunity. Tissue Antigens. 2011; 78(5):321-32. DOI: 10.1111/j.1399-0039.2011.01780.x. View

16.

Hu X, Feng Y, Zhang D, Zhao S, Hu Z, Greshock J . A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell. 2014; 26(3):344-357. PMC: 4159613. DOI: 10.1016/j.ccr.2014.07.009. View

17.

Hsiao Y, Bahn J, Lin X, Chan T, Wang R, Xiao X . Alternative splicing modulated by genetic variants demonstrates accelerated evolution regulated by highly conserved proteins. Genome Res. 2016; 26(4):440-50. PMC: 4817768. DOI: 10.1101/gr.193359.115. View

18.

Allsopp R, Dayl S, Schmid R, Evans R . Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120. Sci Rep. 2017; 7(1):725. PMC: 5429621. DOI: 10.1038/s41598-017-00732-5. View

19.

Fuller S, Stokes L, Skarratt K, Gu B, Wiley J . Genetics of the P2X7 receptor and human disease. Purinergic Signal. 2009; 5(2):257-62. PMC: 2686826. DOI: 10.1007/s11302-009-9136-4. View

20.

Virginio C, MacKenzie A, North R, Surprenant A . Kinetics of cell lysis, dye uptake and permeability changes in cells expressing the rat P2X7 receptor. J Physiol. 1999; 519 Pt 2:335-46. PMC: 2269518. DOI: 10.1111/j.1469-7793.1999.0335m.x. View