PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death.
PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death.
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PIKfyve 调节 CaV1.2 降解并防止兴奋毒性细胞死亡。
DOI：
10.1083/jcb.200903028
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发表时间：
2009-10-19
期刊：
影响因子：
--
通讯作者：
Dolmetsch RE
中科院分区：
文献类型：
--
作者：
Tsuruta F;Green EM;Rousset M;Dolmetsch RE
Neuronal Ca levels are regulated by glutamate receptor activation, which recruits PIKfyve to voltage-gated Ca channels, prompting their degradation. 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.
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影响因子：
5.5
作者：
Davis, SF;Linn, CL
通讯作者：
Linn, CL
影响因子：
4.8
作者：
Lawe, DC;Patki, V;Corvera, S
通讯作者：
Corvera, S
DOI：
10.1083/jcb.143.1.65
发表时间：
1998-10-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gary JD;Wurmser AE;Bonangelino CJ;Weisman LS;Emr SD
通讯作者：
Emr SD
影响因子：
64.8
作者：
Chan, C. Savio;Guzman, Jaime N.;Surmeier, D. James
通讯作者：
Surmeier, D. James
影响因子：
64.5
作者：
Gomez-Ospina, Natalia;Tsuruta, Fuminori;Dolmetsch, Ricardo
通讯作者：
Dolmetsch, Ricardo