Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/ijms22126542
Keywords
anoctamin; ATP sensitization; cell permeabilization; purinergic receptor; ion channel
Funding
- Agence Nationale de la Recherche [ANR-14-CE110004-01]
- Ministere de la Recherche
- International Center for Frontier Research in Chemistry [Labex CSC-TGR-18]
- Region Grand Est
- Ecole Universitaire de Recherche Euridol (Programme d'investissement d'Avenir) [ANR-17-EURE-0022]
- University of Strasbourg Institute for Advanced Study (USIAS)
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Activation of P2X7 receptors leads to various physiological responses, such as the secretion of pro-inflammatory cytokines and modulation of cell death. Current facilitation and macropore formation involve functional complexes that increase P2X7 open probability and mediate large molecule permeation.
P2X7 receptors (P2X7) are cationic channels involved in many diseases. Following their activation by extracellular ATP, distinct signaling pathways are triggered, which lead to various physiological responses such as the secretion of pro-inflammatory cytokines or the modulation of cell death. P2X7 also exhibit unique behaviors, such as macropore formation, which corresponds to enhanced large molecule cell membrane permeability and current facilitation, which is caused by prolonged activation. These two phenomena have often been confounded but, thus far, no clear mechanisms have been resolved. Here, by combining different approaches including whole-cell and single-channel recordings, pharmacological and biochemical assays, CRISPR/Cas9 technology and cell imaging, we provide evidence that current facilitation and macropore formation involve functional complexes comprised of P2X7 and TMEM16, a family of Ca2+-activated ion channel/scramblases. We found that current facilitation results in an increase of functional complex-embedded P2X7 open probability, a result that is recapitulated by plasma membrane cholesterol depletion. We further show that macropore formation entails two distinct large molecule permeation components, one of which requires functional complexes featuring TMEM16F subtype, the other likely being direct permeation through the P2X7 pore itself. Such functional complexes can be considered to represent a regulatory hub that may orchestrate distinct P2X7 functionalities.
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