Fibroblast Growth Factor Receptor 1-5-Hydroxytryptamine 1A Heteroreceptor Complexes and Their Enhancement of Hippocampal Plasticity
Fibroblast Growth Factor Receptor 1-5-Hydroxytryptamine 1A Heteroreceptor Complexes and Their Enhancement of Hippocampal Plasticity
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DOI：
10.1016/j.biopsych.2011.09.012
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发表时间：
2012-01-01
影响因子：
10.6
通讯作者：
Fuxe, Kjell
中科院分区：
文献类型：
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作者：
Borroto-Escuela, Dasiel O.;Romero-Fernandez, Wilber;Fuxe, Kjell
背景：海马区及其5-羟色胺传递在参与边缘环路可塑性的抑郁症中起着重要作用。方法：采用生物发光共振能量转移、免疫共沉淀、原位邻近连接实验、细胞免疫结合实验和强迫游泳实验进行分析。结果：利用生物发光共振能量转移分析，证实了成纤维细胞生长因子受体1(FGFR1)-5-羟色胺1A(5-HT1A)受体复合体的存在，并表征了其特异性和激动剂调节作用。基于免疫共沉淀和邻近连接分析，它们的存在也被证明存在于海马区培养和大鼠的背侧海马区，显示了神经元的位置。体外细胞外信号调节激酶1和2的磷酸化检测表明，与成纤维细胞生长因子2(FGF2)和5-HT1A激动剂共激活信号的协同增加，并依赖于异源受体界面。体外和体内研究还显示，5-HT1A激动剂诱导大鼠海马区FGFR1和细胞外信号调节激酶1/2的磷酸化，而不改变FGF2的水平。异种受体的共激活也导致PC12细胞的延伸以及依赖于受体界面的原代海马区培养的轴突密度和突起的协同增加。在强迫游泳实验中，FGF2和8-OH-DPAT联合急性和重复侧脑室注射可产生非常显著的抗抑郁作用。结论：5-羟色胺在脑内的神经营养和抗抑郁作用可能部分是通过激活海马区FGFR1-5-HT1A受体复合体中的5-HT1a受体启动子促进FGFR1信号转导而实现的。
Background: The hippocampus and its 5-hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity.Methods: The analysis was made with bioluminescence resonance energy transfer, co-immunoprecipitation, in situ proximity ligation assay, binding assay, in cell western and the forced swim test.Results: Using bioluminescence resonance energy transfer analysis, fibroblast growth factor receptor 1 (FGFR1)-5-hydroxytryptamine 1A (5-HT1A) receptor complexes have been demonstrated and their specificity and agonist modulation characterized. Their presence based on co-immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location. In vitro assays on extracellular signal-regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 (FGF2) and a 5-HT1A agonist, and dependent on the heteroreceptor interface. In vitro and in vivo studies also revealed a 5-HT1A agonist induced phosphorylation of FGFR1 and extracellular signal-regulated kinase 1/2 in rat hippocampus without changing FGF2 levels. Co-activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface. The combined acute and repeated intracerebroventricular treatment with FGF2 and 8-OH-DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test.Conclusions: The findings indicate that neurotrophic and antidepressant effects of 5-HT in brain may, in part, be mediated by activation of the 5-HT1A receptor protomer in the hippocampal FGFR1-5-HT1A receptor complex enhancing the FGFR1 signaling.