Cell signaling via the P2X7 nucleotide receptor: linkage to ROS production, gene transcription, and receptor trafficking

Abstract

Extracellular nucleotides can act as important intercellular signals in diverse biological processes, including the enhanced production of factors that are key to immune response regulation. One receptor that binds extracellular adenosine triphosphate released at sites of infection and injury is P2X 7 , which is an ionotrophic receptor that can also lead to the formation of a non-specific pore, activate multiple mitogen-activated protein kinases (MAPKs), and stimulate the production of immune mediators including interleukin family members and reactive oxygen species (ROS). In the present report, we have investigated the signaling mechanisms by which P2X 7 promotes monocytic cell mediator production and induces transcription factor expression/ phosphorylation, as well as how receptor-associated pore activity is regulated by intracellular trafficking. We report that P2X 7 stimulates ROS production in macrophages through the MAPKs ERK1/2 and the nicotinamide adenine dinucleotide phosphate oxidase complex, activates several transcription factors including cyclic-AMP response element-binding protein and components of the activating protein-1 complex, and contains specific sequences within its intracellular C-terminus that appear critical for its activity. Altogether, these data further implicate P2X 7 activation and signaling as a fundamental modulator of macrophage immune responses.

P2X7 receptor activation induces reactive oxygen species formation in erythroid cells

“…P2X7-induced ROS formation has been previously observed in myeloid cells [6][7][8][9][10][11][12]35], glomerular mesangial cells [36] and submandibular gland cells [30,31], but to the best of our knowledge, the current study is the first to demonstrate that P2X7 activation causes ROS formation in erythroid cells. It will be of future importance to determine if P2X7 induces ROS formation in primary erythroid cells.…”

P2X7 Receptor-Dependent Intestinal Afferent Hypersensitivity in a Mouse Model of Postinfectious Irritable Bowel Syndrome

“…This demonstrates that, although P2X 7 Rs do not seem to contribute to basal IL-1b levels, the immune cell environment in the knockout animals (or the lack of P2X 7 R itself) contributes to downregulating both the release of mature IL-1b and the expression of pro-IL-1b in response to infection. This could be well explained by the fact that P2X 7 R stimulation induces MAPK signaling (32)(33)(34), and the expression of pro-IL-1b is strongly dependent on this signaling cascade (8).…”

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

“…The generation of reactive oxygen species (ROS) after ATP activation of P2X7 is now well established in macrophages (Lenertz et al, 2009;Moore and MacKenzie, 2009), microglia (Apolloni et al, 2013;Bartlett et al, 2013), submandibular gland cells (Seil et al, 2008), and erythroid cells (Wang and Sluyter, 2013). Activation of NADPH oxidase 2 by P2X7 was a common feature found in all cell types studied, although there is evidence that ATP, possibly via P2X7 activation, can also enhance mitochondrial reactive oxygen species (Nakahira et al, 2011).…”