Human fibroblasts as a relevant model to study signal transduction in affective disorders.
BACKGROUND
Previous studies have demonstrated a blunted beta adrenoceptor-linked protein kinase A (PKA) response in the 900xg supernatant fraction of human fibroblasts cultured from patients with major depression.


RESULTS
Results of the present studies demonstrate a significant reduction in the B(max) value of [3H]cyclic AMP binding to the regulatory subunit of PKA in the supernatant fraction of fibroblasts from patients with major depression with no change in the K(d) values. The data are consistent with the previous observation that the maximal stimulation of PKA by cyclic AMP is reduced without a change in the EC(50) value. The blunted beta adrenoceptor-mediated PKA response in fibroblasts from patients with major depression is reflected in a significant reduction in the isoproterenol-stimulated phosphorylation of the nuclear transcription factor CREB. Both, the isoproterenol-mediated phosphorylation of nuclear CREB and the activation of the stably transfected luciferase reporter gene, pAD neo2-C12-BGL, were inhibited by the beta(2) adrenoceptor antagonist ICI 118551, thus indicating that the gene activating action of isoproterenol in human fibroblasts is mediated via the beta(2) adrenoceptor cascade. The low EC(50) value of 1 nM isoproterenol for activation of gene expression in stably transfected human fibroblasts appears to be a reflection of the amplification mechanism occurring via the beta adrenoceptor-cyclic AMP-PKA-CREB transduction cascade.


CONCLUSIONS
The results support the notion that human fibroblasts represent a relevant model for studying processes of signal transduction in patients with affective disorders.
Manier
D H
DH
Departments of Psychiatry and Pharmacology, Vanderbilt University Medical Center, 37232, Nashville, TN, USA.
Shelton
R C
RC
Ellis
T C
TC
Peterson
C S
CS
Eiring
A
A
Sulser
F
F
D000318:Adrenergic beta-Agonists / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003865:Major Depressive Disorder / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D017362:Cyclic AMP Response Element-Binding Protein; D011412:Propanolamines; C026777:ICI 118551; D000242:Cyclic AMP; D008156:Luciferases; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol