Borroto-Escuela Dasiel O, Pérez-Alea Mileidys, Narvaez Manuel, Tarakanov Alexander O, Mudó Giuseppa, Jiménez-Beristain Antonio, Agnati Luigi F, Ciruela Francisco, Belluardo Natale, Fuxe Kjell
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Lab Animal Models and Cancer Laboratory Anatomy Pathology Program, Institut de Recerca Vall d'Hebron, 08035 Barcelona, Spain.
Biochem Biophys Res Commun. 2015 Jul 31;463(3):180-6. doi: 10.1016/j.bbrc.2015.04.133. Epub 2015 May 6.
New findings show existence of FGFR1-5-HT1A heteroreceptor complexes in 5-HT nerve cells of the dorsal and median raphe nuclei of the rat midbrain and hippocampus. Synergistic receptor-receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity. The existence of FGFR1-5-HT1A heteroreceptor complexes also in midbrain raphe 5-HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5-HT levels can cause an activation of the FGF-2/FGFR1 mechanism in these nerve cells as well. Therefore, the agonist modulation of the FGFR1-5-HT1A heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5-HT nerve cells. The combined i.c.v. treatment with FGF-2 and the 5-HT1A agonist 8-OHDPAT synergistically increased FGFR1 and ERK1/2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells. Cotreatment with FGF2 and the 5-HT1A agonist induced RN33B cell differentiation as seen from development of an increased number and length of extensions per cell and their increased 5-HT immunoreactivity. These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the 5-HT1A receptor. Taken together, the 5-HT1A autoreceptors by being part of a FGFR1-5-HT1A heteroreceptor complex in the midbrain raphe 5-HT nerve cells appears to have also a trophic role in the central 5-HT neuron systems besides playing a key role in reducing the firing of these neurons.
新发现表明，在大鼠中脑和海马背侧及中缝核的5-羟色胺（5-HT）神经细胞中存在成纤维细胞生长因子受体1（FGFR1）-5-HT1A异源受体复合物。这些受体复合物中的协同受体-受体相互作用表明它们在海马可塑性中具有增强作用。中脑缝际5-HT神经细胞中也存在FGFR1-5-HT1A异源受体复合物，这使得抗抑郁药物通过提高细胞外5-HT水平也能激活这些神经细胞中的成纤维细胞生长因子2（FGF-2）/FGFR1机制成为可能。因此，目前正在大鼠延髓缝际RN33B细胞和富含5-HT神经细胞的中脑尾侧中线缝际区域确定FGFR1-5-HT1A异源受体复合物的激动剂调节作用及其特定作用。脑室内联合给予FGF-2和5-HT1A激动剂8-羟基二苯丙氨酸（8-OHDPAT）可协同增加中脑缝际中线区域和RN33B细胞中FGFR1和细胞外信号调节激酶1/2（ERK1/2）的磷酸化。从每个细胞延伸的数量和长度增加以及5-HT免疫反应性增强可以看出，FGF2和5-HT1A激动剂联合处理诱导了RN33B细胞分化。这些信号传导和分化事件依赖于受体界面，因为它们被5-HT1A受体的TMV孵育阻断，但未被TMII阻断。综上所述，5-HT1A自身受体作为中脑缝际5-HT神经细胞中FGFR1-5-HT1A异源受体复合物的一部分，除了在减少这些神经元的放电中起关键作用外，似乎在中枢5-HT神经元系统中也具有营养作用。
