Encoding and Transducing the Synaptic or Extrasynaptic Origin of NMDA Receptor Signals to the Nucleus

Abstract

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 neurodegeneration. 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 α-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.

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

“…1). Furthermore, synaptic NMDA receptors induce genomic alterations that render neurons more resistant to apoptosis and oxidative insults (Hardingham et al, 2002;Leveille et al, 2010;Kaufman et al, 2012;Karpova et al, 2013). However, the relative role of synaptic and extrasynaptic NMDAR in excitotoxic cell death needs further investigation, considering the conflicting results showing neurotoxicity induced by synaptic NMDAR (Papouin et al, 2012) and the evidence pointing to a role for these receptors in hypoxic excitotoxic death (Wroge et al, 2012).…”

“…The [Ca 2+ ] i overload increases calpain activity with consequent cleavage of several proteins, which contributes to cell death (Araujo et al, 2004;Sanchez-Gomez et al, 2011). Calcium influx through synaptic NMDAR induces signaling pathways which upregulate the transcription of anti-apoptotic genes and genes involved in antioxidant defenses (Hardingham et al, 2002;Leveille et al, 2010;Kaufman et al, 2012;Karpova et al, 2013). In contrast, the excessive activation of extrasynaptic NMDAR induces signaling pathways promoting transcription of pro-apoptotic genes and mitochondrial injury, contributing to excitotoxic cell death (Stanika et al, 2009;Leveille et al, 2010;Kaufman et al, 2012;Wroge et al, 2012).…”

Isolation of CA1 Nuclear Enriched Fractions from Hippocampal Slices to Study Activity-dependent Nuclear Import of Synapto-nuclear Messenger Proteins

“…pS180 Jacob leads to an increased expression of plasticity related genes and this gene expression feeds back to synaptic function. In sharp contrast, Jacob that translocates to the nucleus after extrasynaptic NMDARs activation is not phosphorylated at Ser180 and might be associated with different protein complex in the nucleus causing 'CREB shut off' and a retraction of synaptic contacts 10 .…”

“…Synaptic activity induces ERK1/2 dependent phosphorylation of Jacob at a crucial serine at position 180 (pJacobS 180) which is a requisite for the subsequent translocation to the nucleus in primary hippocampal culture. Moreover, in CA1 neurons of acute hippocampal slices pJacobS 180 translocates to the nucleus after Schaffer collateral LTP but not LTD 1,10 . pS180 Jacob leads to an increased expression of plasticity related genes and this gene expression feeds back to synaptic function.…”

When Synaptic Proteins Meet the Genome: Transcriptional Regulation in Cell Death and Plasticity by the Synapto–Nuclear Messenger Jacob

“…Neuronal importins are present in axons, dendrites, and synapses and they can associate with a dynein motor for active retrograde transport along microtubuli to the nucleus. Jacob utilizes this transport system after activation of both type of receptors and in a recent study we found that Jacob, following its nuclear import, can encode the synaptic and extrasynaptic origin of NMDAR signals (Karpova et al, 2013). ERK1/2-kinase binding and ERK-dependent phosphorylation of the serine180 residue in Jacob encodes synaptic but not extrasynaptic NMDAR activation.…”