Stroth Nikolas, Svenningsson Per
Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institute, 17176 Stockholm, Sweden.
Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institute, 17176 Stockholm, Sweden.
Eur Neuropsychopharmacol. 2015 Dec;25(12):2372-80. doi: 10.1016/j.euroneuro.2015.10.003. Epub 2015 Oct 21.
The serotonin 5-HT7 receptor (5-HT7) is an emerging target for psychiatric pharmacotherapy. Recent observations in rodent models and humans suggest that its blockade mediates antidepressant efficacy. In the present study, we identify the Ca(2+)-binding protein S100B as an interacting partner of 5-HT7 and show that S100B negatively regulates inducible cyclic AMP (cAMP) accumulation in transfected HeLa cells and mouse cortical astrocytes. Overexpression of S100B causes brain region-specific dysregulation of the cAMP pathway in vivo, such that concentrations of cAMP in the frontal cortex are higher in S100B transgenic female mice compared to wild-types. Finally, S100B transgenic female mice show depressive-like behavior in the forced swim test (FST) and pharmacological blockade of 5-HT7 with SB269970 normalizes FST behavior. Taken together, our results show that S100B affects behavioral despair in female mice through functional interaction with the 5-HT7 receptor. Furthermore, we identify S100B as a cAMP-regulatory protein in cultured astrocytes and the murine frontal cortex. Future experiments will clarify whether there is a direct link between the 5-HT7-associated and cAMP-regulatory actions of S100B.
血清素5-HT7受体（5-HT7）是精神科药物治疗中一个新出现的靶点。最近在啮齿动物模型和人类中的观察表明，阻断该受体可介导抗抑郁疗效。在本研究中，我们鉴定出钙结合蛋白S100B是5-HT7的相互作用蛋白，并表明S100B在转染的HeLa细胞和小鼠皮质星形胶质细胞中负向调节诱导型环磷酸腺苷（cAMP）的积累。S100B的过表达在体内导致cAMP信号通路的脑区特异性失调，使得S100B转基因雌性小鼠额叶皮质中的cAMP浓度高于野生型。最后，S100B转基因雌性小鼠在强迫游泳试验（FST）中表现出类似抑郁的行为，用SB269970对5-HT7进行药理学阻断可使FST行为恢复正常。综上所述，我们的结果表明，S100B通过与5-HT7受体的功能相互作用影响雌性小鼠的行为绝望。此外，我们确定S100B是培养的星形胶质细胞和小鼠额叶皮质中的一种cAMP调节蛋白。未来的实验将阐明S100B与5-HT7相关的作用和cAMP调节作用之间是否存在直接联系。
