The anti-apoptotic, glucocorticoid receptor cochaperone protein BAG-1 is a long-term target for the actions of mood stabilizers.
Increasing data suggest that impairments of cellular plasticity/resilience underlie the pathophysiology of bipolar disorder. A series of microarray studies with validating criteria have recently revealed a common, novel target for the long-term actions of the structurally highly dissimilar mood stabilizers lithium and valproate: BAG-1 [BCL-2 (B-cell CLL/lymphoma 2)-associated athanogene]. Because BAG-1 attenuates glucocorticoid receptor (GR) nuclear translocation, activates ERK (extracellular signal-regulated kinase) MAP (mitogen-activated protein) kinases, and potentiates anti-apoptotic functions of BCL-2, extensive additional studies were undertaken. Chronic administration of both agents at therapeutic doses increased the expression of BAG-1 in rat hippocampus. Furthermore, these findings were validated at the protein level, and the effects were seen in a time frame consistent with therapeutic effects and were specific for mood stabilizers. Functional studies showed that either lithium or valproate, at therapeutically relevant levels, inhibited dexamethasone-induced GR nuclear translocation and inhibited GR transcriptional activity. Furthermore, small interfering RNA studies showed that these inhibitory effects on GR activity were mediated, at least in part, through BAG-1. The observation that BAG-1 inhibits glucocorticoid activation suggests that mood stabilizers may counteract the deleterious effects of hypercortisolemia seen in bipolar disorder by upregulating BAG-1. Additionally, these studies suggest that regulation of GR-mediated plasticity may play a role in the treatment of bipolar disorder and raise the possibility that agents affecting BAG-1 more directly may represent novel therapies for this devastating illness.
Zhou
Rulun
R
Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Bethesda, Maryland 20852, USA.
Gray
Neil A
NA
Yuan
Peixiong
P
Li
Xiaoxia
X
Chen
Jingshan
J
Chen
Guang
G
Damschroder-Williams
Patricia
P
Du
Jing
J
Zhang
Lei
L
Manji
Husseini K
HK
D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007211:Indoles / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D008970:Molecular Weight; D009447:Neuroblastoma; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D014635:Valproic Acid / Q000494:pharmacology*
D018692:Antimanic Agents; C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D007211:Indoles; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; C007293:DAPI; D014635:Valproic Acid; D003907:Dexamethasone; D008094:Lithium; D000469:Alkaline Phosphatase