人們常說的“腦子越用越靈”有其內(nèi)在的神經(jīng)生物學(xué)基礎(chǔ)，神經(jīng)活動能夠促進(jìn)神經(jīng)元的發(fā)育和網(wǎng)絡(luò)功能構(gòu)建,，神經(jīng)營養(yǎng)因子可能在其中發(fā)揮重要作用,。神經(jīng)元通過軸突輸出信息，通過樹突接受并整合大量的由突觸介導(dǎo)的信息輸入,，但其形態(tài)發(fā)生機(jī)制尚不完全清楚,。10月28日，美國《國家科學(xué)院院刊》（PNAS）在線發(fā)表了中科院神經(jīng)科學(xué)研究所的最新研究成果,，揭示了一種神秘的酶在神經(jīng)元形態(tài)發(fā)生中的作用,。
異戊二烯基轉(zhuǎn)移酶Geranylgeranyltransferase I (GGT)因能夠介導(dǎo)蛋白的翻譯后脂化修飾，從而導(dǎo)致多種信號蛋白 (包括 Rho家族的小G蛋白) 的膜轉(zhuǎn)運,，成為腫瘤治療的靶點,，但在神經(jīng)系統(tǒng)的作用完全未知。在羅振革研究員指導(dǎo)下,，博士生周秀萍等對該酶在神經(jīng)發(fā)育中的作用進(jìn)行了深入研究,。周秀萍等發(fā)現(xiàn)神經(jīng)活動和腦源性神經(jīng)營養(yǎng)因子(BDNF)增強(qiáng)GGT的活性，后者引起Rac小G蛋白的膜轉(zhuǎn)運,，Rac的膜定位對于后繼激活以及樹突分支是必需的,。進(jìn)而發(fā)現(xiàn)GGT與BDNF的受體TrkB具有直接相互作用并受神經(jīng)活動的調(diào)節(jié)，阻斷TrkB與GGT的相互作用可以抑制神經(jīng)元去極化和BDNF引起的樹突發(fā)育增加,。另外,，把實驗鼠放在新奇的環(huán)境中能使海馬區(qū)GGT的活性快速升高，同時促進(jìn)Rac的膜定位,。該研究揭示了神經(jīng)活動和BDNF促進(jìn)樹突發(fā)育的新機(jī)制,。
該項工作得到國家科技部、自然科學(xué)基金委,、上海市科委及科學(xué)院的支持,，歷時3年完成。（生物谷Bioon.com）
生物谷推薦原始出處：
PNAS,，doi: 10.1073/pnas.0800846105,，Xiu-Ping Zhou, Zhen-Ge Luo
TrkB-mediated activation of geranylgeranyltransferase I promotes dendritic morphogenesis
Xiu-Ping Zhou, Kong-Yan Wu, Bin Liang, Xiu-Qing Fu, and Zhen-Ge Luo1
Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Abstract
Dendrite morphogenesis is regulated by neuronal activity or neurotrophins, which may function by activating intrinsic signaling proteins, including Rho family GTPases. Here we report that activity- and brain-derived neurotrophic factor (BDNF)–dependent dendritic morphogenesis requires activation of geranylgeranyltransferase I (GGT), a prenyltransferase that mediates lipid modification of Rho GTPases. Dendritic arborization in cultured hippocampal neurons was promoted by over-expression of GGT, and reduced by inhibition or down-regulation of GGT. Furthermore, GGT was activated by neuronal depolarization or BDNF, both of which promote dendritic arborization, in cultured hippocampal neurons. Moreover, exploration of a novel environment caused activation of GGT in the mice hippocampus, suggesting that neural activity activates GGT in vivo. Interestingly, GGT was physically associated with tropomyosin-related kinase B (TrkB), the receptor for BDNF, and this association was enhanced by depolarization. Disrupting the GGT-TrkB interaction or down-regulating GGT activity attenuated depolarization- or BDNF-induced dendrite development. Finally, the GGT effect on dendrite arborization was prevented by over-expressing Rac1 with the prenylation site deleted or mutated. Thus depolarization- or BDNF-dependent dendrite development may be mediated by GGT-induced prenylation of Rho GTPases.
