Abstract
P2X purinergic receptors are extracellular ATP-gated ion channel receptors present on the cell plasma membrane. P2X receptors have been found in Metazoa, fungi, amoebas, and in plants. In mammals, P2X7 is expressed by a large number of cell types and is involved in inflammation and immunity. Remarkably, P2X7 does not desensitize as other P2X do, a feature linked to a “C-cysteine anchor” intra-cytoplasmic motif encoded by exon 11. Another specific feature of P2X7 is its C-terminal cytoplasmic ballast domain (exon 13) which contains a zinc (Zn) coordinating cysteine motif and a GDP-binding region. To determine the origin of P2X7, we analyzed and compared sequences and protein motifs of the C-terminal intra-cytoplasmic region across all main groups of Metazoa. We identified proteins with typical ballast domains, sharing a remarkably conserved Zn-coordinating cysteine motif. Apart from vertebrates, these ballast domains were not associated with a typical P2X architecture. These results strongly suggest that P2X7 resulted from the fusion of a P2X gene, highly similar to P2X4, with an exon encoding a ballast domain. Our work brings new evidence on the origin of the P2X7 purinergic receptor and identifies the Zn-coordinating cysteine domain as the fundamental feature of the ancient ballast fold.
Highlights
The P2X7 receptor is the seventh member of the P2X receptor family of ATP-gated cation channels
For example in Origin of P2X7 Ballast Domain macrophages activated by bacterial products, the main cell death induced via P2X7R stimulation is pyroptosis [(7–9), reviewed in [10]]
P2X7 is found across vertebrates from bony fish to mammals combining a P2X domain, a putative C-cys anchor and a ballast domain while the other P2X receptors lack the two last features
Summary
The P2X7 receptor is the seventh member of the P2X receptor family of ATP-gated cation channels. P2X7 activation requires higher ATP concentrations (0.5 to 1 mM) than for other members of the P2XR family; required concentrations are nanomolar for P2X1 and P2X3, and micromolar for P2X2 and P2X4. Prolonged ligation of P2X7 results in the formation of non-selective pores in the plasma membrane, permeable to molecules up to 900 Da. Prolonged ATP ligation of P2X7 can trigger membrane blebbing [1] and cell death by apoptosis [2] or lysis/necrosis [3,4,5,6] depending on the cell type. For example in Origin of P2X7 Ballast Domain macrophages activated by bacterial products, the main cell death induced via P2X7R stimulation is pyroptosis [(7–9), reviewed in [10]]. The role of P2X7 in inflammation and infectious diseases has been the subject of numerous studies and has been reviewed thoroughly [10, 23]
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