title: Lithium inhibits caspase 3 activation and dephosphorylation of PKB and GSK3 induced by K+ deprivation in cerebellar granule cells.
abstract: Lithium protects cerebellar granule cells from apoptosis induced by low potassium, and also from other apoptotic stimuli. However, the precise mechanism by which this occurs is not understood. When cerebellar granule cells were switched to low potassium medium, the activation of caspase 3 was detected within 6 h, suggesting a role of caspase 3 in mediating apoptosis under conditions of low potassium. In the same conditions, lithium (5 mM) inhibited the activation of caspase 3 induced by low potassium. As lithium did not inhibit caspase 3 activity in vitro, these results suggest that this ion inhibits an upstream component that is required for caspase 3 activation. Lithium is known to inhibit a kinase termed glycogen sythase kinase 3 (GSK3), which is implicated in the survival pathway of phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB). Here we demonstrate that low potassium in the absence of lithium induces the dephosphorylation, and therefore the activation, of GSK3. However, when lithium was present, GSK3 remained phosphorylated at the same level as observed under conditions of high potassium. Low potassium induced the dephosphorylation and inactivation of PKB, whereas when lithium was present PKB was not dephosphorylated. Our results allow us to propose a new hypothesis about the action mechanism of lithium, this ion could inhibit a serine-threonine phosphatase induced by potassium deprivation.
authors: Departamento de Bioquímica y Biología Molecular, Facultad de Veterinaria, Universidad de Extremadura, Avenue Universidad s/n, 10071 Cáceres, Spain.
authors: A
authors: A
authors: Mora
authors: G
authors: G
authors: Sabio
authors: R A
authors: RA
authors: González-Polo
authors: A
authors: A
authors: Cuenda
authors: D R
authors: DR
authors: Alessi
authors: J C
authors: JC
authors: Alonso
authors: J M
authors: JM
authors: Fuentes
authors: G
authors: G
authors: Soler
authors: F
authors: F
authors: Centeno
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3; D008094:Lithium / Q000494:pharmacology*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011191:Potassium Deficiency / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar
chemical_list: D011518:Proto-Oncogene Proteins; D008094:Lithium; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases