P2X7 Variants in Pathophysiology

Abstract

P2X7 receptor activation by extracellular adenosine triphosphate (eATP) modulates different intracellular pathways, including pro-inflammatory and tumor-promoting cascades. ATP is released by cells and necrotic tissues during stressful conditions and accumulates mainly in the inflammatory and tumoral microenvironments. As a consequence, both the P2X7 blockade and agonism have been proposed as therapeutic strategies in phlogosis and cancer. Nevertheless, most studies have been carried out on the WT fully functional receptor variant. In recent years, the discovery of P2X7 variants derived by alternative splicing mechanisms or single-nucleotide substitutions gave rise to the investigation of these new P2X7 variants' roles in different processes and diseases. Here, we provide an overview of the literature covering the function of human P2X7 splice variants and polymorphisms in diverse pathophysiological contexts, paying particular attention to their role in oncological and neuroinflammatory conditions.

Keywords: P2X7; SNP; cancer; inflammation; splice variants; therapy resistance.

Figure 1

Differential behavior of cancer cells expressing P2X7A and P2X7B. Anticancer treatment with chemotherapy and radiotherapy induces the release of a high amount of ATP in the tumor microenvironment. Cancer cells expressing P2X7A in the presence of elevated levels of ATP undergo cell death due to the opening of the pore while P2X7B-expressing cells are not affected by the cytotoxic effect of ATP. The surviving cells proliferate and allow the relapse of the disease after treatment, promoting a more aggressive cancer that spreads and forms metastases in distant sites from the primary tumor.