Chronic carbamazepine treatment increases myristoylated alanine-rich C kinase substrate phosphorylation in the rat cerebral cortex via down-regulation of calcineurin A alpha.
Carbamazepine (CBZ) is generally used as a mood-stabilizing drug for the treatment of bipolar disorders. However, little is known about the molecular mechanisms of CBZ actions in the brain, which account for this therapeutic profile. In the present study, we examined the effects of chronic CBZ treatment on the protein kinase C (PKC) pathway. Male Wistar rats received injections of CBZ once daily for 3-5 weeks. The protein levels of PKC isozymes, calcineurin Aalpha subunit (CaN-Aalpha) and myristoylated alanine-rich C kinase substrate (MARCKS), and phosphorylation of MARCKS in the rat cerebral cortex were determined by immunoblot analysis. The content of CaN-Aalpha mRNA was determined by Northern blot analysis. Nomicr; significant changes were observed in PKC alpha, beta, gamma, delta and epsilon in the cytosol and membrane fractions after 5 weeks of CBZ treatment. There were no significant changes in the actin-binding PKCepsilon. Interestingly, phosphorylation of MARCKS was increased more than twofold, while no significant changes were observed in MARCKS protein level in the cytosol fraction. Furthermore, CaN-Aalpha was significantly decreased at both the protein and mRNA levels. The level of MARCKS phosphorylation is reportedly regulated by the balance between PKC-mediated phosphorylation and CaN-mediated dephosphorylation. Our results indicate that chronic CBZ treatment increases MARCKS phosphorylation via decreasing the content of CaN-Aalpha. Phosphorylation of MARCKS has been reported to play an important role in the release of neurotransmitters, such as noradrenaline and serotonin. Therefore, the increase in phosphorylation of MARCKS observed only after chronic CBZ treatment may be related to the mood-stabilizing effects of CBZ.
Hasegawa
Hiroshi
H
Department of Neuropsychiatry, St. Marianna University School of Medicine, 2-16-1 Sugao, Kawasaki, Kanagawa, Miyamae 216-8511, Japan. k2osada@marianna-u.ac.jp
Osada
Kenichi
K
Misonoo
Atusi
A
Morinobu
Sigeru
S
Yamamoto
Hideyuki
H
Miyamoto
Eishichi
E
Asakura
Mikio
M
D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002220:Carbamazepine / Q000008:administration & dosage*; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D047908:Intracellular Signaling Peptides and Proteins; C000619712:Marcks protein, rat; D008565:Membrane Proteins; D021122:Protein Subunits; D011506:Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D002220:Carbamazepine; D019703:Calcineurin