P2X7 nucleotide receptor is coupled to GSK-3 inhibition and neuroprotection in cerebellar granule neurons.
In this study we report the coupling of nucleotide receptors to GSK-3 signalling, a relevant survival pathway in cerebellar granule neurons. P2X(7) agonist BzATP induced a 3-4-fold increase in GSK-3 phosphorylation, which is reported to be associated with the catalytic activity inhibition. This effect was dependent on extracellular calcium and PKC, and independent of PI3-K (phosphatidyl-inositol-3-kinase)/Akt, the main survival route of neurotrophins. BzATP also prevented the apoptosis of granule neurons induced by the pharmacological inhibition of the PI3-K signalling. Both effects, BzATP-mediated GSK-3 phosphorylation and neuroprotection, were abolished by P2X(7) receptor antagonists, BBG, PPADS and A-438079. We found that BzATP prevented the progressive GSK-3 dephosphorylation and caspase-3 activation occurring under conditions of sustained PI3-K inhibition. These results reveal that P2X(7) receptor activation could provide a relevant survival route alternative to classical neurotrophic factors.
Ortega
Felipe
F
Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria, Universidad Complutense de Madrid, Avda. Puerta de Hierro s/n, Madrid 28040, Spain.
Pérez-Sen
Raquel
R
Delicado
Esmerilda G
EG
Miras-Portugal
M Teresa
MT
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D020287:In Situ Nick-End Labeling / Q000379:methods; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D013997:Time Factors
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D010975:Platelet Aggregation Inhibitors; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D011732:Pyridoxal Phosphate; C045674:2',3'-O-(2,4,6-trinitro-cyclohexadienylidine)adenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3; D002118:Calcium