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

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.

The role of the purinergic ligand-gated ion channel 7 receptor in common digestive system cancers

“…and the extracellular ATP-binding site (McCarthy et al, 2019). P2X7R is composed of three P2X7 subunits (De Salis et al, 2022). And the P2X7R consists of five main components: N-terminal Cytosolic Tail, C-terminal Cytosolic Tail, First Transmembrane Domain TM1, Second Transmembrane Domain TM2 and Extracellular Domain (Surprenant et al, 1996).…”

“…At present, seven types of P2XR have been identified: P2X1R~P2X7R (Sluyter, 2017). Purinergic ligand-gated ion channel 7 receptor (P2X7R) is widely distributed and highly expressed in immune cells and hematopoietic cells, such as monocytes, macrophages, mast cells, eosinophils and basophils (Wiley et al ., 2011; Savio et al ., 2018; De Salis et al ., 2022). Among P2Rs, P2X7R appears to be the main participant in host-tumor cell interaction, and preclinical studies in several tumor models suggest that targeting P2X7R may be an effective anticancer therapy (Di Virgilio et al ., 2018a).…”

“…When briefly stimulated with low concentrations of ATP, the receptors form cation channels to Na + , K + and Ca 2+ . However, when repeated or prolonged stimulation with high concentrations of ATP, P2X7R form large pores in the plasma membrane that allow passage of molecules as large as 900 Da, such as ethidium bromide and YO-PRO (Gartland et al ., 2001; Lenertz et al ., 2011; Mehta et al ., 2014; Di Virgilio and Adinolfi, 2017a; Ziberi et al ., 2019; De Salis et al ., 2022). P2X7R leads to a dual effect of cell proliferation (survival) and cell death (cytolysis), which is influenced by ATP concentration (Martinez-Cuesta et al ., 2020).…”

“…studied the electron microscopic structure of rat P2X7R in both the open and closed states, presenting for the first time an understanding of the complete P2X7R structure, including the intracellular structure and the extracellular ATP-binding site (McCarthy et al ., 2019). P2X7R is composed of three P2X7 subunits (De Salis et al ., 2022). And the P2X7R consists of five main components: N-terminal Cytosolic Tail, C-terminal Cytosolic Tail, First Transmembrane Domain TM1, Second Transmembrane Domain TM2 and Extracellular Domain (Surprenant et al ., 1996).…”

Purinergic Signalling in Physiology and Pathophysiology

“…De Salis et al [12] review the gene and protein structures of the human and murine P2X7 receptors, and their isoforms, including an in-depth description of alternative splicing processes and single nucleotide polymorphisms, which give rise to the various P2X7 isoforms. They present a detailed table of 14 human P2X7 isoforms, providing a valuable resource for further studies.…”