Human fibroblasts as a relevant model to study signal transduction in affective disorders
Human fibroblasts as a relevant model to study signal transduction in affective disorders
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DOI：
10.1016/s0165-0327(99)00190-1
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发表时间：
2000-12-01
影响因子：
6.6
通讯作者：
Sulser, F
中科院分区：
文献类型：
--
作者：
Manier, DH;Shelton, RC;Sulser, F
背景：以前的研究表明，重度抑郁症患者的人成纤维细胞培养上清液中900倍的β-肾上腺素受体相关蛋白激酶A(PKA)反应迟钝。结果：抑郁症患者成纤维细胞上清液中[H-3]cAMP与PKA调节亚基结合的B-max值显著降低，而K-d值无明显变化。这些数据与先前的观察结果一致，即环化AMP对PKA的最大刺激作用降低，而EC50值不变。重度抑郁症患者成纤维细胞中β受体介导的PKA反应迟钝，反映在异丙肾上腺素刺激的核转录因子CREB的磷酸化显著减少。β(2)肾上腺素受体拮抗剂ICI 118551可抑制异丙肾上腺素介导的核CREB的磷酸化和稳定表达的荧光素酶报告基因pAD ne2-C12-bgl的激活，表明异丙肾上腺素对人成纤维细胞的基因激活作用是通过β(2)肾上腺素受体级联途径实现的。在稳定表达的人成纤维细胞中，1 nM异丙肾上腺素激活Gent表达的低EC50值似乎反映了通过β肾上腺素受体-环状AMP-PKA-CREB转导级联发生的扩增机制。结论：该结果支持人成纤维细胞是研究情感性精神障碍患者信号转导过程的相关模型的观点。(C)2000 Elsevier Science B.V.保留所有权利。
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 previous 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 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 EC50 value of 1 nM isoproterenol for activation of gent 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 fur studying processes of signal transduction in patients with affective disorders. (C) 2000 Elsevier Science B.V. All rights reserved.