Chronic treatment of astrocytes with therapeutically relevant fluoxetine concentrations enhances cPLA2 expression secondary to 5-HT2B-induced, transactivation-mediated ERK1/2 phosphorylation
Chronic treatment of astrocytes with therapeutically relevant fluoxetine concentrations enhances cPLA2 expression secondary to 5-HT2B-induced, transactivation-mediated ERK1/2 phosphorylation
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用治疗相关的氟西汀浓度长期治疗星形胶质细胞可增强继发于 5-HT2B 诱导、反式激活介导的 ERK1/2 磷酸化的 cPLA2 表达
DOI：
10.1007/s00213-009-1631-3
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发表时间：
2009-11-01
影响因子：
3.4
通讯作者：
Peng, Liang
中科院分区：
文献类型：
--
作者：
Li, Baoman;Zhang, Shiquen;Peng, Liang
我们最近发现，氟西汀（一种选择性5 - 羟色胺再摄取抑制剂，SSRI）在小鼠星形胶质细胞原代培养中对5 - HT2C受体具有低微摩尔亲和力（但对5 - HT2A和5 - HT2B受体没有）。这是通过表皮生长因子（EGF）受体的转激活介导的磷酸化作用，即细胞外调节激酶1和2（ERK1/2）的磷酸化（刺激）来确定的，随后是常规的EGF受体信号传导（Li等人，《精神药理学》194:333 - 334, 2007）。帕罗西汀具有相同的作用。本研究表明，以更高亲和力（半数有效浓度EC50 = 0.5 - 2.0 μM）进行的慢性氟西汀治疗会上调Ca²⁺依赖性磷脂酶A₂（cPLA₂），它从膜结合磷脂的sn - 2位置释放花生四烯酸，而对分泌型磷脂酶A₂（sPLA₂）和细胞内磷脂酶A₂（iPLA₂）没有影响。这一证明重复了Rao等人（《药物基因组学杂志》6:413 - 420, 2006）所展示的氟西汀诱导的大鼠大脑中cPLA₂的上调，并提供了新的信息，即上调（1）发生在星形胶质细胞中，（2）是由5 - HT2B受体的刺激引起的，（3）需要转激活介导的ERK1/2磷酸化。在抗抑郁治疗期间，由于血清素水平升高和/或SSRI通过5 - HT2介导的信号传导，完整大脑中cPLA₂的类似上调可能解释了反复报道的SSRI使重度抑郁症期间大脑代谢中出现的区域性降低正常化的能力，因为（1）花生四烯酸强烈刺激培养的星形胶质细胞中的葡萄糖代谢（Yu等人，《神经科学研究杂志》64:295 - 303, 1993），以及（2）抑郁症患者血浆中花生四烯酸的浓度与局部大脑葡萄糖代谢呈线性相关（Elizabeth Sublette等人，《前列腺素、白细胞三烯及必需脂肪酸》80:57 - 64, 2009）。
We have recently shown that fluoxetine, a serotonin-specific reuptake inhibitor (SSRI), has low micromolar affinity for the 5-HT2C receptor (but not for 5-HT2A and 5-HT2B receptors) in primary cultures of mouse astrocytes. This was determined as phosphorylation (stimulation) of extracellular-regulated kinase 1 and 2 (ERK1/2) by transactivation-mediated phosphorylation of the epidermal growth factor (EGF) receptor, followed by conventional EGF receptor signaling (Li et al., Psychopharmacology 194:333-334, 2007). Paroxetine has an identical effect. The present study shows that chronic fluoxetine treatment with even higher affinity (EC50 = 0.5-2.0 A mu M) upregulates Ca2+-dependent phospholipase A(2) (cPLA(2)), which releases arachidonic acid from the sn-2 position of membrane-bound phospholipid, without effect on secretory PLA(2) (sPLA(2)) and intracellular PLA(2) (iPLA(2)).This demonstration replicates the fluoxetine-induced cPLA(2) upregulation in rat brain shown by Rao et al. (Pharmacogenomics J 6:413-420, 2006) and provides the new information that upregulation (1) occurs in astrocytes, (2) is evoked by stimulation of 5-HT2B receptor, and (3) requires transactivation-mediated ERK1/2 phosphorylation. Similar upregulation of cPLA(2) in intact brain in response to 5-HT2-mediated signaling by elevated serotonin levels and/or an SSRI during antidepressant treatment may explain the repeatedly reported ability of SSRIs to normalize regional decreases which occur in brain metabolism during major depression, since (1) arachidonic acid strongly stimulates glucose metabolism in cultured astrocytes (Yu et al., J Neurosci Res 64:295-303, 1993) and (2) plasma concentrations of arachidonic acid in depressed patients are linearly correlated with regional brain glucose metabolism (Elizabeth Sublette et al., Prostaglandins Leukot Essent Fatty Acids 80:57-64, 2009).