Regulation of GSK-3beta by calpain in the 3-nitropropionic acid model.
Glycogen synthase kinase-3beta (GSK-3beta) is a crucial component in the cascade of events that culminate in a range of neurodegenerative diseases. It is controlled by several pathways, including calpain-mediated cleavage. Calpain mediates in cell death induced by 3-nitropropionic acid (3-NP), but GSK-3beta regulation has not been demonstrated. Here we studied changes in total GSK-3beta protein levels and GSK-3beta phosphorylation at Ser-9 in this model. The 3-NP treatment induced GSK-3beta truncation. This regulation was dependent on calpain activation, since addition of calpeptin to the medium prevented this cleavage. While calpain inhibition prevented 3-NP-induced neuronal loss, inhibition of GSK-3beta by SB-415286 did not. Furthermore, inhibition of cdk5, a known target of calpain involved in 3-NP-induced cell death, also failed to rescue neurons in our model. Our results point to a new target of calpain and indicate possible cross-talk between calpain and GSK-3beta in the 3-NP toxicity pathway. On the basis of our findings, we propose that calpain may modulate 3-NP-induced neuronal loss.
Crespo-Biel
N
N
Unitat de Farmacologia i Farmacognòsia, Institut de Biomedicina, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, E-08028 Barcelona, Spain.
Camins
A
A
Gutiérrez-Cuesta
J
J
Melchiorri
D
D
Nicoletti
F
F
Pallàs
M
M
Canudas
A M
AM
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D002154:Calpain / Q000378:metabolism* / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003292:Convulsants / Q000633:toxicity*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009574:Nitro Compounds / Q000633:toxicity*; D011422:Propionates / Q000633:toxicity*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D000077546:Roscovitine; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000590:Amino Acid Chloromethyl Ketones; D000627:Aminophenols; D003292:Convulsants; D004791:Enzyme Inhibitors; D008301:Maleimides; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D011422:Propionates; D011687:Purines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000077546:Roscovitine; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D002154:Calpain; D020169:Caspases; C015392:3-nitropropionic acid