7月4日《神經(jīng)科學(xué)雜志》（Journal of Neuroscience）發(fā)表了中科院上海生科院神經(jīng)所王以政研究組題為“經(jīng)典型瞬時(shí)電壓受體通道5通過a亞型鈣調(diào)蛋白激酶2介導(dǎo)神經(jīng)營(yíng)養(yǎng)因子3對(duì)大鼠海馬神經(jīng)元樹突生長(zhǎng)的調(diào)控作用”的研究論文,。該論文報(bào)道了神經(jīng)營(yíng)養(yǎng)因子3 （Neurotrophin-3， NT-3）通過開放經(jīng)典型瞬時(shí)電壓受體通道5（Transient receptor potential canonical 5， TRPC5）引起細(xì)胞外鈣離子內(nèi)流,，進(jìn)一步通過下游的鈣離子相關(guān)蛋白a亞型鈣調(diào)蛋白激酶2（Calmodulin-dependent kinase IIa,， CaMKIIa）抑制海馬神經(jīng)元樹突生長(zhǎng)發(fā)育的的新機(jī)制,。該工作是由神經(jīng)所的賀焯皓博士等人在王以政研究員的指導(dǎo)下完成的,。
NT-3是一類富集于大腦中的神經(jīng)營(yíng)養(yǎng)因子，具有很多重要的生理功能,，且這些功能中很多都和NT-3引起的神經(jīng)元內(nèi)鈣信號(hào)增加有關(guān),。然而NT-3是如何引起神經(jīng)元內(nèi)的鈣信號(hào)增加卻一直不清楚。另一方面,，TRPC這樣一類鈣離子通透的非選擇性陽離子通道被越來越多的證據(jù)提示為一類新的細(xì)胞內(nèi)鈣信號(hào)的來源,。相對(duì)于分布廣泛的TRPC其他亞家族成員，TRPC5蛋白較為集中地表達(dá)于中樞神經(jīng)系統(tǒng),，且存在于中樞神經(jīng)系統(tǒng)中的TRPC5通道的生理性的激動(dòng)劑是未知的,。
在這項(xiàng)研究中，王以政組的研究人員通過免疫組化,、基因干擾,、實(shí)時(shí)活細(xì)胞鈣信號(hào)成像、神經(jīng)元形態(tài)分析以及生物化學(xué)等手段發(fā)現(xiàn)NT-3可以通過受體TrkC以及細(xì)胞膜內(nèi)的g型磷脂酶C （Phospholipase Cg,， PLCg）開放TRPC5并特異調(diào)控了神經(jīng)元內(nèi)鈣調(diào)蛋白激酶CaMKIIa的活性,，從而實(shí)現(xiàn)對(duì)海馬神經(jīng)元樹突生長(zhǎng)發(fā)育的抑制作用。同時(shí),，他們發(fā)現(xiàn)了另外一種神經(jīng)營(yíng)養(yǎng)因子 （Neurotrophin-4,， NT-4）對(duì)海馬神經(jīng)元樹突生長(zhǎng)發(fā)育起著促進(jìn)的作用,，且這樣的調(diào)控作用可能是通過NT-4開放TRPC6后激活CaMKIV實(shí)現(xiàn)的,。
這項(xiàng)工作闡述了NT-3引起的神經(jīng)元內(nèi)鈣信號(hào)的機(jī)制，也提示了NT-3是TRPC5通道位于中樞神經(jīng)系統(tǒng)內(nèi)的一種的生理性的激動(dòng)劑,。同時(shí),，該工作也揭示了不同的神經(jīng)營(yíng)養(yǎng)因子通過不同的鈣離子通道分別激活不同的下游鈣離子效應(yīng)分子，以此實(shí)現(xiàn)對(duì)神經(jīng)元樹突生長(zhǎng)發(fā)育的陰陽調(diào)控的新機(jī)制,。
該課題受到了中科院,、科技部“973項(xiàng)目”以及中國(guó)國(guó)家自然科學(xué)基金的資助。
（生物谷Bioon.com）
doi:10.1523/JNEUROSCI.6363-11.2012
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TRPC5 Channel Is the Mediator of Neurotrophin-3 in Regulating Dendritic Growth via CaMKIIα in Rat Hippocampal Neurons
Zhuohao He1,2, Caixia Jia1, Shengjie Feng1,2, Kechun Zhou1, Yilin Tai1, Xue Bai1,2, and Yizheng Wang1
Neurotrophin-3 (NT-3) plays numerous important roles in the CNS and the elevation of intracellular Ca2+ ([Ca2+]i) is critical for these functions of NT-3. However, the mechanism by which NT-3 induces [Ca2+]i elevation remains largely unknown. Here, we found that transient receptor potential canonical (TRPC) 5 protein and TrkC, the NT-3 receptor, exhibited a similar temporal expression in rat hippocampus and cellular colocalization in hippocampal neurons. Stimulation of the neurons by NT-3 induced a nonselective cation conductance and PLCγ-dependent [Ca2+]i elevation, which were both blocked when TRPC5, but not TRPC6 channels, were inhibited. Moreover, the Ca2+ influx through TRPC5 induced by NT-3 inhibited the neuronal dendritic growth through activation of calmodulin-dependent kinase (CaMK) IIα. In contrast, the Ca2+ influx through TRPC6 induced by NT-4 promoted the dendritic growth. Thus, TRPC5 acts as a novel and specific mediator for NT-3 to regulate dendrite development through CaMKIIα.
