@article{a8ab1692a87840ad99d7765f2d9f3a72,
title = "Ras and Rap Signal Bidirectional Synaptic Plasticity via Distinct Subcellular Microdomains",
abstract = "How signaling molecules achieve signal diversity and specificity is a long-standing cell biology question. Here we report the development of a targeted delivery method that permits specific expression of homologous Ras-family small GTPases (i.e., Ras, Rap2, and Rap1) in different subcellular microdomains, including the endoplasmic reticulum, lipid rafts, bulk membrane, lysosomes, and Golgi complex, in rodent hippocampal CA1 neurons. The microdomain-targeted delivery, combined with multicolor fluorescence protein tagging and high-resolution dual-quintuple simultaneous patch-clamp recordings, allows systematic analysis of microdomain-specific signaling. The analysis shows that Ras signals long-term potentiation via endoplasmic reticulum PI3K and lipid raft ERK, whereas Rap2 and Rap1 signal depotentiation and long-term depression via bulk membrane JNK and lysosome p38MAPK, respectively. These results establish an effective subcellular microdomain-specific targeted delivery method and unveil subcellular microdomain-specific signaling as the mechanism for homologous Ras and Rap to achieve signal diversity and specificity to control multiple forms of synaptic plasticity. Zhang et al. develop an effective subcellular microdomain-specific targeted delivery method and demonstrate that homologous proteins (e.g., Ras and Rap) confine their signaling within distinct subcellular microdomains to achieve signal transduction diversity and specificity.",
keywords = "AMPA-R phorphorylation, AMPA-R trafficking, GluA1, GluA2, GluA2L, GluA4, nanocluster, organelle fractionation, subcellular signaling",
author = "Lei Zhang and Peng Zhang and Guangfu Wang and Huaye Zhang and Yajun Zhang and Yilin Yu and Mingxu Zhang and Jian Xiao and Piero Crespo and Hell, {Johannes W.} and Li Lin and Huganir, {Richard L.} and Zhu, {J. Julius}",
note = "Funding Information: We thank the members of the Zhu laboratory for comments and technical assistance and Drs. Ian Macara and Roger Tsien for reagents and/or use of lab resources. This study was supported in part by a Virginia Center on Aging postdoctoral ARDRAF award (to L.Z.); Epilepsy Foundation Postdoctoral Fellowship 310443 (to G.W.); MINECO/FEDER-UE grant SAF-2015-63638R, RTICC grant RD-12-0036-0033, and AECC grant GCB141423113 (to P.C.); National Natural Science Foundation of China grants NSFC81722028 (to J.X.) and NSFC81771284 (to L.L.); HHMI (to R.L.H.); NIH grants NS036715 (to R.L.H.), NS065183 and NS089578 (to H.Z.), NS078792 (to J.W.H.), and NS053570, NS091452, NS094980, NS092548, and NS104670 (to J.J.Z.). J.J.Z. is a Radboud Professor and Sir Yue-Kong Pao Chair Professor. Funding Information: We thank the members of the Zhu laboratory for comments and technical assistance and Drs. Ian Macara and Roger Tsien for reagents and/or use of lab resources. This study was supported in part by a Virginia Center on Aging postdoctoral ARDRAF award (to L.Z.); Epilepsy Foundation Postdoctoral Fellowship 310443 (to G.W.); MINECO/FEDER-UE grant SAF-2015-63638R , RTICC grant RD-12-0036-0033 , and AECC grant GCB141423113 (to P.C.); National Natural Science Foundation of China grants NSFC81722028 (to J.X.) and NSFC81771284 (to L.L.); HHMI (to R.L.H.); NIH grants NS036715 (to R.L.H.), NS065183 and NS089578 (to H.Z.), NS078792 (to J.W.H.), and NS053570 , NS091452 , NS094980 , NS092548 , and NS104670 (to J.J.Z.). J.J.Z. is a Radboud Professor and Sir Yue-Kong Pao Chair Professor. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = may,
day = "16",
doi = "10.1016/j.neuron.2018.03.049",
language = "English (US)",
volume = "98",
pages = "783--800.e4",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "4",
}