Human erythrocytes release ATP by a novel pathway involving VDAC oligomerization independent of pannexin-1.
Irene Marginedas-FreixaCora Lilia AlvarezMartina MorasMaría Florencia Leal DenisClaude HattabFrançois HalleFrédéric BihelIsabelle Mouro-ChanteloupSophie Denise LefevreCaroline Le Van KimPablo Julio SchwarzbaumMariano Anibal OstuniPublished in: Scientific reports (2018)
We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transport complex in human red blood cells (RBCs). Because VDAC was proposed as a channel mediating ATP release in RBCs, we used TSPO ligands together with VDAC and ANT inhibitors to test this hypothesis. ATP release was activated by TSPO ligands, and blocked by inhibitors of VDAC and ANT, while it was insensitive to pannexin-1 blockers. TSPO ligand increased extracellular ATP (ATPe) concentration by 24-59% over the basal values, displaying an acute increase in [ATPe] to a maximal value, which remained constant thereafter. ATPe kinetics were compatible with VDAC mediating a fast but transient ATP efflux. ATP release was strongly inhibited by PKC and PKA inhibitors as well as by depleting intracellular cAMP or extracellular Ca2+, suggesting a mechanism involving protein kinases. TSPO ligands favoured VDAC polymerization yielding significantly higher densities of oligomeric bands than in unstimulated cells. Polymerization was partially inhibited by decreasing Ca2+ and cAMP contents. The present results show that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by a supramolecular complex involving VDAC, TSPO2 and ANT.
Keyphrases
- pet imaging
- endothelial cells
- binding protein
- protein kinase
- induced apoptosis
- red blood cell
- computed tomography
- liver failure
- heart rate
- small molecule
- cell cycle arrest
- positron emission tomography
- blood pressure
- cell death
- acute respiratory distress syndrome
- resistance training
- high intensity
- extracorporeal membrane oxygenation
- cell proliferation