Reduced CREB phosphorylation after chronic lithium treatment is associated with down-regulation of CaM kinase IV in rat hippocampus.
Lithium is widely used in the treatment of bipolar disorder, although its mechanism of action is not fully clear. This study was undertaken to assess the effects of prolonged lithium administration on cAMP responsive element-binding protein (CREB) phosphorylation and CaM kinase IV (CaMKIV), one of the main kinases phosphorylating CREB in neurons following synaptic activation. CREB total protein expression and phosphorylation (Ser133), as well as CaMKIV enzymatic activity, phosphorylation of Thr196 (the activator residue) and kinase expression level were assessed in total homogenates and nuclei from the hippocampus and prefrontal/frontal cortex following 5 wk lithium treatment. Whereas no significant effects were found in prefrontal/frontal cortex, lithium administration reduced CREB phosphorylation and at the same time down-regulated CaMKIV (enzymatic activity, phospho-Thr196 and protein expression level) in cell nuclei from the hippocampus. These data suggest for the first time the involvement of CaMKIV in the mechanism of action of lithium.
Tardito
Daniela
D
Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milano, Italy. daniela.tardito@unimi.it
Tiraboschi
Ettore
E
Kasahara
Jiro
J
Racagni
Giorgio
G
Popoli
Maurizio
M
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015536:Down-Regulation; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016651:Lithium Carbonate / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D018692:Antimanic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D016651:Lithium Carbonate; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517686:Camk4 protein, rat