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

Autor: Francisco Andrés Peralta, Eric Boué-Grabot, Kate Dunning, Fanny Gautherat, Thierry Chataigneau, Vincent Compan, Patrick Wolf, Adeline Martz, Federico Cevoli, Thomas Grutter
Přispěvatelé: Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Boué-Grabot, Eric, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Cell Membrane Permeability
Phospholipid scramblase
[SDV]Life Sciences [q-bio]
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Cell
purinergic receptor
anoctamin
Adenosine Triphosphate
0302 clinical medicine
Biology (General)
Spectroscopy
0303 health sciences
Chemistry
Purinergic receptor
ATP sensitization
General Medicine
Immunohistochemistry
Computer Science Applications
Cholesterol
medicine.anatomical_structure
cell permeabilization
Facilitation
Signal transduction
P2X7
Algorithms
QH301-705.5
Anoctamins
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Models
Biological
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
medicine
Extracellular
Animals
Humans
Secretion
Physical and Theoretical Chemistry
QD1-999
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
Molecular Biology
Ion channel
030304 developmental biology
Cell Membrane
Organic Chemistry
[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
HEK293 Cells
ion channel
Oocytes
Biophysics
Receptors
Purinergic P2X7
CRISPR-Cas Systems
030217 neurology & neurosurgery
Zdroj: International Journal of Molecular Sciences
International Journal of Molecular Sciences, MDPI, 2021, 22 (12), pp.6542. ⟨10.3390/ijms22126542⟩
International Journal of Molecular Sciences, 2021, 22 (12), pp.6542. ⟨10.3390/ijms22126542⟩
International Journal of Molecular Sciences, Vol 22, Iss 6542, p 6542 (2021)
Volume 22
Issue 12
ISSN: 1422-0067
1661-6596
Popis: International audience; 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.
Databáze: OpenAIRE
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