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 900 x g 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 [H-3]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 previou s observation that the maximal stimulation of PKA by cyclic AMP is reduced without a change in the EC50 value. The blunted beta adrenoceptor-mediated PKA response in fibroblasts from patients with major depression is reflecte d in a significant reduction in the isoproterenol-stimulated phosphorylatio n of the nuclear transcription factor CREB. Both, the isoproterenol-mediate d phosphorylation of nuclear CREB and the activation of the stably transfec ted luciferase reporter gene, pAD neo2-C12-BGL, were inhibited by the beta( 2) adrenoceptor antagonist ICI 118551, thus indicating that the gene activa ting action of isoproterenol in human fibroblasts is mediated via the beta( 2) adrenoceptor cascade. The low EC50 value of 1 nM isoproterenol for activ ation of gent expression in stably transfected human fibroblasts appears to be a reflection of the amplification mechanism occurring via the beta adre noceptor-cyclic AMP-PKA-CREB transduction cascade. Conclusions: The results support the notion that human fibroblasts represent a relevant model fur s tudying processes of signal transduction in patients with affective disorde rs. (C) 2000 Elsevier Science B.V. All rights reserved.