Extracellular histone proteins are novel activators of P2XR7 channel current
PHYSIOLOGY(2023)
Abstract
Extracellular histone proteins have been identified as important damage associated molecules that contribute to vascular dysfunction. Histones are elevated in circulation after traumatic injury and activation of the innate immune response. In prior work, we demonstrated that extracellular histone proteins induced endothelial cell (EC) Ca 2+ influx, increased EC propidium iodide labeling, and decreased vasodilatory responses. These paradoxical observations could be explained by activation of a non-selective cation channel. The ionotropic purinergic receptor 7 (P2XR7) stands out as a candidate as it has been shown to form a high-conductance, poorly selective, cation channel capable of conducting large cationic dyes. Herein, we test the hypothesis that P2XR7 channels are activated by histone proteins. We expressed mouse P2XR7 (C57BL/6J variant 451L) in heterologous cells ( Xenopus oocytes) and measured inward cation current using two-electrode voltage clamp (TEVC). Cells expressing mouse P2XR7 had robust ATP- and histone-evoked inward cation currents. ATP- and histone-evoked currents reversed approximately at the same potential. Current decay with agonist removal was much slower for histone-evoked than ATP- or BzATP-evoked currents. As with ATP-evoked P2XR7 currents, histone-evoked currents were inhibited by non-selective P2XR7 antagonists (Suramin, PPADS, and TNP-ATP). GW791343, a selective P2XR7 antagonist with a known binding site distinct from the ATP binding site, inhibited ATP-evoked currents but did not inhibit histone-evoked currents. As with ATP-evoked currents, histone-evoked P2XR7 currents were also increased in conditions of low extracellular Ca 2+ . These data demonstrate that P2XR7 is necessary and sufficient for histone-evoked inward cation currents. These results suggest a new allosteric mechanism of P2XR7 activation by histone proteins that may guide the development of more effective P2XR7 pharmacology and therapeutic strategies for a wide array of pathologies that involve P2XR7 function. DMC is supported by NIH R00HL133451 and R01HL155180 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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Key words
p2xr7 channel current,extracellular histone proteins
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