Drug-induced decrease of protein kinase a activity reveals alteration in BDNF expression of bipolar affective disorder.
Bipolar affective disorder (BAD) is a severe disease whose molecular and cellular bases are not well known. The aim of the present study was to probe the cAMP signaling downstream targets by pharmacologically manipulating the protein kinase A (PKA) enzyme, along with the assessment of brain-derived neurotrophic factor (BDNF) expression in lymphoblasts. The time course of lymphoblast PKA activity (up to 72 h) revealed optimal activity at 24 h. Then, the enzyme activity and protein levels of PKA Calpha subunit and phopsho-cAMP responsive element binding (CREB) were assayed in lymphoblasts derived from 12 BAD and 12 control (CT) subjects and cultured for 24 h in the presence of cAMP analog drugs. The results indicated that basal PKA activity and PKA Calpha subunit immunolabeling are increased in cells from BAD compared with controls. Enzyme activity was increased by Sp-isomer in BAD and in CT's cells, without change in protein levels. In contrast, the Rp-isomer decreased enzyme activity and protein levels. In drug-naive conditions, there was no change in BDNF expression of BAD cells compared with CT cells. Treatment with Sp-isomer induced increased BDNF in both groups, while treatment with Rp-isomer induced a significant decrease in BDNF expression of BAD compared with CT. The p-CREB changes followed changes in BDNF levels, with increased and decreased Sp-isomer and Rp-isomer treatment, respectively. Our results suggest that mood disorder is associated with PKA upregulation and this could mask alteration in BDNF expression, because slowing down of PKA signaling results in a decrease of BDNF expression. These findings, combined with previous reports, provide a new insight to explain pharmacological features in different diagnostic groups.
Karege
Félicien
F
Geneva University Hospitals (Belle-Idéé), Division of Neuropsychiatry, Chêne-Bourg (Geneva), Switzerland. felicien.karege@biolo.unige.ch
Schwald
Michèle
M
El Kouaissi
Rachid
R
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D051697:Activating Transcription Factor 1; D000328:Adult; D001714:Bipolar Disorder / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western / Q000379:methods; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D021122:Protein Subunits / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D051697:Activating Transcription Factor 1; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D021122:Protein Subunits; D012333:RNA, Messenger; D014157:Transcription Factors; D015124:8-Bromo Cyclic Adenosine Monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases