P2X7 Interactions and Signaling – Making Head or Tail of It

Abstract

Extracellular adenine nucleotides play important roles in cell–cell communication and tissue homeostasis. High concentrations of extracellular ATP released by dying cells are sensed as a danger signal by the P2X7 receptor, a non-specific cation channel. Studies in P2X7 knockout mice and numerous disease models have demonstrated an important role of this receptor in inflammatory processes. P2X7 activation has been shown to induce a variety of cellular responses that are not usually associated with ion channel function, for example changes in the plasma membrane composition and morphology, ectodomain shedding, activation of lipases, kinases, and transcription factors, as well as cytokine release and apoptosis. In contrast to all other P2X family members, the P2X7 receptor contains a long intracellular C-terminus that constitutes 40% of the whole protein and is considered essential for most of these effects. So far, over 50 different proteins have been identified to physically interact with the P2X7 receptor. However, few of these interactions have been confirmed in independent studies and for the majority of these proteins, the interaction domains and the physiological consequences of the interactions are only poorly described. Also, while the structure of the P2X7 extracellular domain has recently been resolved, information about the organization and structure of its C-terminal tail remains elusive. After shortly describing the structure and assembly of the P2X7 receptor, this review gives an update of the identified or proposed interaction domains within the P2X7 C-terminus, describes signaling pathways in which this receptor has been involved, and provides an overlook of the identified interaction partners.

Deletion of P2X7 Receptor Decreases Basal Glutathione Level by Changing Glutamate-Glutamine Cycle and Neutral Amino Acid Transporters

“…There is no experimental evidence or literature concerning P2X7R interactions with xCT. However, over 50 different proteins have been identified to physically interact with P2X7R, since P2X7R contains a long intracellular C-terminus that constitutes 40% of the whole protein [47]. In particular, P2X7R activation results in translocation of the Ca 2+ -dependent PKC isoforms, such as PKCα and PKCβI, but not the Ca 2+ -independent isoform PKCδ in osteoclasts [48].…”

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

“…The P2X7R C-terminal tail constitutes about 40% of the whole protein, and its deletion or massive truncation prevents effects mediated by receptor activation such as dye uptake and membrane blebbing (generation of exosomes) but also alters channel kinetics (Kopp et al, 2019). In addition, the C-terminus was implicated in regulating signaling pathway activation, protein-protein interactions, and posttranslational modification (Costa-Junior et al, 2011).…”

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

“…Although RT-PCR analysis has identified P2X4R expression in pancreatic acinar and ductal cells (Luo et al, 1999;Novak et al, 2002) and lacrimal gland acinar cells Kamada et al, 2012), its functional role in exocrine tissues remains largely unexplored. Physical interactions between P2X4Rs and P2X7Rs have been demonstrated, although the nature of this interaction remains controversial (Kopp et al, 2019). Some studies suggest that P2X4R and P2X7R subunits form heteromeric channels (Guo et al, 2007;Schneider et al, 2017), while others conclude that P2X4 and P2X7 receptors interact in their respective homotrimeric form (Nicke, 2008;Boumechache et al, 2009;Antonio et al, 2011).…”