Extracellular human cathelicidin peptide (LL-37) activates P2X7 receptor current

P2X7 is a unique member of the ionotropic purinergic receptor (P2X) family with low affinity for ATP. Increasing evidence suggests that non-nucleotide agonists, such as antimicrobial peptides (AMPs), can also activate P2X7. In this study, we investigated the direct activation of P2X7 currents by the human cathelicidin peptide (LL-37) in Xenopus oocytes expressing human (h.P2X7) or mouse (m.P2X7) P2X7. Extracellular application of LL-37 induced dose-dependent, reversible, currents in h.P2X7- and m.P2X7-expressing cells. A peptide composed of a scrambled LL-37 amino acid sequence did not activate P2X7 currents. LL-37 did not induce current in control oocytes, demonstrating that P2X7 is required for peptide-activated currents. We next tested the effect of orthosteric and allosteric P2X7 antagonists on peptide-activated currents. LL-37-evoked currents were inhibited by orthosteric antagonists (PPADS, Suramin, TNP-ATP) but were unaffected by the most potent allosteric P2X7 antagonists (AZ10606120, A438079). These findings provide new insight into the non-nucleotide modulation of P2X7 and its potential roles in host defense and inflammatory responses. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.