The P2X₇ receptor is a trimeric, ligand-gated ion channel found in a wide variety of cell types, such as neuronal, blood, endothelial, and muscle cells. As part of the purinergic type 2 receptor family, P2X₇ signaling is triggered by the binding of extracellular ATP. As P2X₇ mediates a variety of downstream cellular pathways, including synaptic transmission, platelet activation, inflammation, and apoptosis, it is unsurprising that dysfunctional expression of this receptor has been implicated in many diseases like chronic pain, depression, and cancer. As a result, there is immense interest in the discovery of P2X₇ agonists and antagonists as a way to modulate the function of this receptor for therapeutic purposes.

Unlike the other six P2X family members, P2X₇ is an unusual membrane protein because of its low affinity for ATP and utter lack of desensitization. Previously, insight into P2X₇ signaling and its cytotoxic activity remained elusive due to lack of knowledge regarding the structure and function of its cytoplasmic domain. Recently, however, the structure of P2X₇ was solved using cryoEM in a paper published by the Mansoor research group in Cell. In the article, researchers elegantly characterized and revealed several important insights pertaining to P2X₇'s large cytoplasmic domain. They found that the ATP binding site on apo-P2X₇ appears to be narrower compared to the control apo-P2X3 receptor, restricting solvent/ligand access to the binding site, perhaps justifying P2X₇'s low affinity for ATP. They also identified two structural elements within the cytoplasmic domain that they termed the C-cys anchor and the cytoplasmic ballast. They additionally observed that residues within the C-cys anchor were palmitoylated, and that this modification may contribute to the lack of receptor desensitization by stabilizing the formation of a cytoplasmic cap. The researchers also noted that the cytoplasmic ballast possessed a novel protein fold, and unexpectedly found, within this structural feature, a di-nuclear zinc ion complex, as well as a guanosine nucleotide binding site. While the roles of these features have yet to be understood, their presence is essential for distinguishing P2X₇ function from the other P2X receptor subtypes.

This structural study sets the stage for further investigation into not only the ion channel activity of P2X₇, but also how its sizable cytoplasmic domain may play a direct and important role in downstream cell signaling activity. Better understanding of P2X₇ function and the signaling cascades associated with this receptor will ultimately be able to guide drug discovery efforts of novel therapeutics for diseases associated with aberrant P2X₇ activity.

Alanna E. McCarthy, Craig Yoshioka, Steven E. Mansoor. Full-Length P2X₇ Structures Reveal How Palmitoylation Prevents Channel Desensitization. Cell, 2019; DOI: 10.1016/j.cell.2019.09.017

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