斯坦福大學醫(yī)學院Tsuruta等人發(fā)現(xiàn)一種脂質(zhì)激酶能夠引導電壓門控鈣通道（voltage-gated calcium channel）的退化，從而使得神經(jīng)元免受鈣過量產(chǎn)生的致命影響,。這項研究結(jié)果發(fā)布在2009年10月19日的Journal of Cell Biology上。
在細胞信號傳導中,，鈣是一個重要的參與者,，但其在高水平的時候同樣也有嚴重的毒性。神經(jīng)細胞已經(jīng)進化出自己的方式避免鈣大量進入細胞,。一種限制鈣進入的方式是移除細胞表面的管家（gatekeepers）,，鈣通道。
神經(jīng)細胞指導該過程的機制在臨床上具有重要意義,，該過程紊亂會產(chǎn)生一些嚴重的問題,，比如中風，帕金森氏癥和阿爾茨海默病,。
在對CaV1.2通道的綁定對象進行蛋白質(zhì)組掃描后,，Tsuruta等人首次篩選出了一種脂質(zhì)激酶PIKfyve，其能夠產(chǎn)生PI(3,5)P2,，促進核內(nèi)體（endosomes）到溶酶體（lysosomes）的成熟,。
研究人員猜想，PIKfyve可能引導CaV1.2的退化,。他們使用谷氨酸鹽興奮模擬興奮性壓迫,，結(jié)果表明,，CaV1.2是內(nèi)在化的,，且與PIKfyve相關(guān),，能在溶酶體中退化。當研究人員抑制PIKfyve 和PI(3,5)P2的水平時,，細胞表面出現(xiàn)了過多的通道，這使得神經(jīng)細胞容易凋亡,。
這項研究闡述了神經(jīng)的自我保護機制,，同時表明，現(xiàn)有的鈣通道阻滯藥物可能使病人免遭神經(jīng)組織退化紊亂相關(guān)疾病的影響,。（生物谷Bioon.com）
生物谷推薦原始出處：
The Journal of Cell Biology, Vol. 187, No. 2, 279-294 doi:10.1083/jcb.200903028
PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death
Fuminori Tsuruta, Eric M. Green, Matthieu Rousset, and Ricardo E. Dolmetsch
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305
Voltage-gated Ca2+ channels (VGCCs) play a key role in neuronal signaling but can also contribute to cellular dysfunction and death under pathological conditions such as stroke and neurodegenerative diseases. We report that activation of N-methyl-D-aspartic acid receptors causes internalization and degradation of CaV1.2 channels, resulting in decreased Ca2+ entry and reduced toxicity. CaV1.2 internalization and degradation requires binding to phosphatidylinositol 3-phosphate 5-kinase (PIKfyve), a lipid kinase which generates phosphatidylinositol (3,5)-bisphosphate (PtdIns(3,5)P2) and regulates endosome and lysosome function. Sustained activation of glutamate receptors recruits PIKfyve to CaV1.2 channels, increases cellular levels of PtdIns(3,5)P2, and promotes targeting of CaV1.2 to lysosomes. Knockdown of PIKfyve prevents CaV1.2 degradation and increases neuronal susceptibility to excitotoxicity. These experiments identify a novel mechanism by which neurons are protected from excitotoxicity and provide a possible explanation for neuronal death in diseases caused by mutations that affect PtdIns(3,5)P2 regulation.
