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Article

P2X7 Receptors and TMEM16 Channels Are Functionally Coupled with Implications for Macropore Formation and Current Facilitation

1
CNM Team, Centre National de la Recherche Scientifique, CAMB UMR 7199, Faculté de Pharmacie, Université de Strasbourg, 67401 Illkirch, France
2
Institute for Advanced Studies (USIAS), University of Strasbourg, 67000 Strasbourg, France
3
Institut des Maladies Neurodégénératives, Université de Bordeaux, UMR 5293, 33000 Bordeaux, France
4
Institut des Maladies Neurodégénératives, CNRS, UMR 5293, 33000 Bordeaux, France
5
Institut de Génomique Fonctionnelle (IGF), Université de Montpellier, CNRS, INSERM, 34094 Montpellier, France
6
Laboratoire d’Excellence Canaux Ioniques d’Intérêt Thérapeutique (LabEx ICST), 34094 Montpellier, France
7
Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives, UPR-3212, Université de Strasbourg, 67000 Strasbourg, France
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Ronald Sluyter
Int. J. Mol. Sci. 2021, 22(12), 6542; https://doi.org/10.3390/ijms22126542
Received: 18 May 2021 / Revised: 4 June 2021 / Accepted: 7 June 2021 / Published: 18 June 2021
(This article belongs to the Special Issue Purinergic P2 Receptors: Structure and Function 2.0)
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. View Full-Text
Keywords: P2X7; anoctamin; ATP sensitization; cell permeabilization; purinergic receptor; ion channel P2X7; anoctamin; ATP sensitization; cell permeabilization; purinergic receptor; ion channel
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MDPI and ACS Style

Dunning, K.; Martz, A.; Peralta, F.A.; Cevoli, F.; Boué-Grabot, E.; Compan, V.; Gautherat, F.; Wolf, P.; Chataigneau, T.; Grutter, T. P2X7 Receptors and TMEM16 Channels Are Functionally Coupled with Implications for Macropore Formation and Current Facilitation. Int. J. Mol. Sci. 2021, 22, 6542. https://doi.org/10.3390/ijms22126542

AMA Style

Dunning K, Martz A, Peralta FA, Cevoli F, Boué-Grabot E, Compan V, Gautherat F, Wolf P, Chataigneau T, Grutter T. P2X7 Receptors and TMEM16 Channels Are Functionally Coupled with Implications for Macropore Formation and Current Facilitation. International Journal of Molecular Sciences. 2021; 22(12):6542. https://doi.org/10.3390/ijms22126542

Chicago/Turabian Style

Dunning, Kate, Adeline Martz, Francisco A. Peralta, Federico Cevoli, Eric Boué-Grabot, Vincent Compan, Fanny Gautherat, Patrick Wolf, Thierry Chataigneau, and Thomas Grutter. 2021. "P2X7 Receptors and TMEM16 Channels Are Functionally Coupled with Implications for Macropore Formation and Current Facilitation" International Journal of Molecular Sciences 22, no. 12: 6542. https://doi.org/10.3390/ijms22126542

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