Department of Restorative Neurosurgery, Kanazawa University Graduate School of Medical Science, Takara-machi 13-1, Kanazawa 920-8641, Japan.
Prog Lipid Res. 2012 Jul;51(3):221-31. doi: 10.1016/j.plipres.2012.02.001. Epub 2012 Feb 17.
Despite the well-known effects of polyunsaturated fatty acids (PUFA) on synaptic plasticity, PUFA-modulated signaling mechanism is unknown especially in humans. In 2003, three groups reported that G protein-coupled receptor 40 (GPR40) induces Ca²⁺ mobilization in response to PUFA. Although GPR40 gene is abundantly expressed in the primate brain, it is negligible in the rodent brain. Diverse PUFA including docosahexaenoic acid (DHA) are in vitro ligands for GPR40, but nobody knows its downstream pathway. cAMP-response element binding protein (CREB) is a transcription factor transmitting extracellular signals to change gene expression. Although PUFA, transported by fatty acid binding proteins (FABP), directly phosphorylate CREB in rodents, hydrophobic PUFA cannot access to the nuclei in the primate neurons because of lack of a cargo protein. Ischemia-enhanced adult neurogenesis in monkeys showed concomitant upregulation of GPR40 and phosphorylated CREB, and localization of both in the neurogenic niche. Here, 'PUFA-GPR40-CREB signaling' hypothesis was highlighted as a regulator of adult neurogenesis specific for primates.
尽管多不饱和脂肪酸 (PUFA) 对突触可塑性的影响众所周知，但特别是在人类中，PUFA 调节的信号机制尚不清楚。2003 年，三组研究人员报告称，G 蛋白偶联受体 40 (GPR40) 可响应 PUFA 诱导 Ca²⁺动员。尽管 GPR40 基因在灵长类动物大脑中大量表达，但在啮齿动物大脑中几乎不存在。包括二十二碳六烯酸 (DHA) 在内的多种 PUFA 是 GPR40 的体外配体，但没有人知道其下游途径。环磷酸腺苷反应元件结合蛋白 (CREB) 是一种转录因子，可将细胞外信号传递到细胞核内以改变基因表达。尽管 PUFA 可被脂肪酸结合蛋白 (FABP) 转运，但在啮齿动物中，PUFA 可直接磷酸化 CREB，但由于缺乏货物蛋白，亲脂性 PUFA 无法进入灵长类神经元的细胞核。猴子的缺血增强成年神经发生显示 GPR40 和磷酸化 CREB 同时上调，并且两者都定位于神经发生龛中。在这里，“PUFA-GPR40-CREB 信号”假说被强调为灵长类动物特有的成年神经发生调节剂。
