P2X7 Interactions and Signaling - Making Head or Tail of It.

Robin Kopp,Anna Krautloher,Antonio Ramírez-Fernández,Annette Nicke

doi:10.3389/fnmol.2019.00183

Robin Kopp, Anna Krautloher + Show 2 more

Open Access

https://doi.org/10.3389/fnmol.2019.00183

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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.

Highlights

The ATP-gated P2X receptors are trimeric ion channels with inter-subunit ATP-binding sites (Kaczmarek-Hájek et al, 2012)
A single P2X subunit has been structurally compared to a dolphin (Figure 1A) and contains two α-helical transmembrane domains that are linked by a large extracellular domain [269–288 amino acids long] that is mostly formed by β-sheets and several loop domains (Kawate et al, 2009)
In case of the ATP-bound open state of the human P2X3 receptor, a structure of these intracellular domains has been obtained so far (Mansoor et al, 2016). In this ATPbound structure, the N- and C-termini form a network of three β-sheets that is capping the cytoplasmic side of the pore

Summary

INTRODUCTION

The ATP-gated P2X receptors are trimeric ion channels with inter-subunit ATP-binding sites (Kaczmarek-Hájek et al, 2012). In the search for domains in the P2X7 C-terminus that control P2X7 channel function, pore forming properties, and plasma membrane expression, truncated P2X7 versions were investigated (Smart et al, 2003) and it was found that 95% (i.e., the sequence up to residue 581) of the rat P2X7 C-terminus are required to mediate ethidium uptake in HEK293 cells. The human loss-of-function SNP, I568N, was reported to prevent receptor trafficking and cell surface expression [see Section “Trafficking and Lipid Interaction Domains (∼Residues 540–595)”] (Wiley et al, 2003), supposedly because of its localization within a sequence [DFAI(568)L] (Wiley et al, 2011) similar to a dileucine motif – [D/E]xxxL[I/L]– [(Kozik et al, 2010), compare Section “The Death Domain (∼Residues 430–530)”]. For the majority of the identified proteins, the interaction domains and the physiological consequences of this

Method

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CONCLUSION