The activation of N-methyl-D-aspartate-receptors (NMDARs) in synapses provides plasticity and cell survival signals, whereas NMDARs residing in the neuronal membrane outside synapses trigger neuro-degeneration. At present, it is unclear how these opposing signals are transduced to and discriminated by the nucleus. In this study, we demonstrate that Jacob is a protein messenger that encodes the origin of synaptic versus extrasynaptic NMDAR signals and delivers them to the nucleus. Exclusively synaptic, but not extrasynaptic, NMDAR activation induces phosphorylation of Jacob at serine-180 by ERK1/2. Long-distance trafficking of Jacob from synaptic, but not extrasynaptic, sites depends on ERK activity, and association with fragments of the intermediate filament alpha-internexin hinders dephosphorylation of the Jacob/ERK complex during nuclear transit. In the nucleus, the phosphorylation state of Jacob determines whether it induces cell death or promotes cell survival and enhances synaptic plasticity.
[1]Leibniz Inst Neurobiol, RG Neuroplast, D-39118 Magdeburg, Germany.
[2]Leibniz Inst Neurobiol, Special Lab Electron & Laserscanning Microscopy, D-39118 Magdeburg, Germany.
[3]Leibniz Inst Neurobiol, Dept Neurochem & Mol Biol, D-39118 Magdeburg, Germany.
[4]Univ Utrecht, Fac Sci, NL-3584 CH Utrecht, Netherlands.
[5]Fudan Univ, Inst Brain Sci, Shanghai 200032, Peoples R China.
[6]Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China.
[7]Univ Magdeburg, Inst Expt Internal Med, D-39120 Magdeburg, Germany.
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