Regulation of signal transduction pathways by mood-stabilizing agents: implications for the delayed onset of therapeutic efficacy.
A series of investigations were performed to elucidate the mechanisms of action of lithium, valproate, and carbamazepine. We have found that lithium exerts major effects on G proteins, most likely via a posttranslational process stabilizing the inactive heterotrimeric (alpha beta gamma) form of the protein. We also find that chronic lithium and valproate exert major, very similar effects on the PKC signaling pathway, with both drugs decreasing the levels of membrane-associated PKC alpha and epsilon, and have similar effects on the DNA binding activity of the transcription factor, AP-1. By contrast, we find that carbamazepine exerts major, direct inhibitory effect at the level of adenylyl cyclases. Overall, the results suggest that signal transduction pathways are targets for the actions of mood-stabilizing agents; given their key roles in the amplification and integration of signals in the central nervous system, these findings have clear implications not only for research into the etiology/pathophysiology of manic-depressive illness, but also for the development of innovative treatment strategies.
Manji
H K
HK
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Chen
G
G
Hsiao
J K
JK
Risby
E D
ED
Masana
M I
MI
Potter
W Z
WZ
D000262:Adenylyl Cyclases / Q000187:drug effects; D000818:Animals; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D002220:Carbamazepine / Q000494:pharmacology*; D002460:Cell Line; D019204:GTP-Binding Proteins / Q000187:drug effects*; D005910:Glioma / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D011493:Protein Kinase C / Q000187:drug effects; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014635:Valproic Acid / Q000494:pharmacology*
D017981:Receptors, Neurotransmitter; D002220:Carbamazepine; D014635:Valproic Acid; D008094:Lithium; D008156:Luciferases; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases