Ring finger protein 10 is a novel synaptonuclear messenger encoding activation of NMDA receptors in hippocampus

Abstract

Synapses and nuclei are connected by bidirectional communication mechanisms that enable information transfer encoded by macromolecules. Here, we identified RNF10 as a novel synaptonuclear protein messenger. RNF10 is activated by calcium signals at the postsynaptic compartment and elicits discrete changes at the transcriptional level. RNF10 is enriched at the excitatory synapse where it associates with the GluN2A subunit of NMDA receptors (NMDARs). Activation of synaptic GluN2A-containing NMDARs and induction of long term potentiation (LTP) lead to the translocation of RNF10 from dendritic segments and dendritic spines to the nucleus. In particular, we provide evidence for importin-dependent long-distance transport from synapto-dendritic compartments to the nucleus. Notably, RNF10 silencing prevents the maintenance of LTP as well as LTP-dependent structural modifications of dendritic spines.DOI: http://dx.doi.org/10.7554/eLife.12430.001

The differences between GluN2A and GluN2B signaling in the brain

“…Ring finger protein 10 (RNF10) and Jacob are involved in the signaling transduction processes of GluN2A and GluN2B, respectively. GluN2A, but not GluN2B, directly interacts with RNF10, and the C‐terminal region (991–1049) of GluN2A as well as the N‐terminal region (1–221) of RNF10 are crucial for the binding (Dinamarca et al, ). The GluN2A‐RNF10 signaling pathway plays an important role in the maintenance of NMDAR‐dependent long‐term potentiation (LTP) as well as LTP‐dependent structural modifications of dendritic spines (Dinamarca et al, ).…”

“…GluN2A, but not GluN2B, directly interacts with RNF10, and the C‐terminal region (991–1049) of GluN2A as well as the N‐terminal region (1–221) of RNF10 are crucial for the binding (Dinamarca et al, ). The GluN2A‐RNF10 signaling pathway plays an important role in the maintenance of NMDAR‐dependent long‐term potentiation (LTP) as well as LTP‐dependent structural modifications of dendritic spines (Dinamarca et al, ). GluN2B, but not GluN2A, forms a complex with Jacob and CaMKIIα (Melgarejo da Rosa, Yuanxiang, Brambilla, Kreutz, & Karpova, ).…”

“…The GluN2A-RNF10 signaling pathway plays an important role in the maintenance of NMDAR-dependent long-term potentiation (LTP) as well as LTP-dependent structural modifications of dendritic spines (Dinamarca et al, 2016 Table 2). The differences in the effects on the above signaling molecules and related signaling pathways of GluN2A and GluN2B were discussed in the following paragraphs.…”

Regulated transport of signaling proteins from synapse to nucleus

“…This systematic approach led to the discovery of AIDA-1 as a synaptonuclear signaling protein that translocates to the nucleus after NMDAR activation to regulate nucleolar numbers and protein synthesis [19]. More recently, Dinamarca et al characterized protein binding partners of the cytoplasmic tail of the GluN2A subunit of NMDARs, and identified the ring finger protein RNF10 as a novel binding partner [20]. The authors then demonstrated that RNF10 translocates to the nucleus during LTP to regulate gene expression.…”

“…This evidence suggests that importins shuttle cargo from synapse-to-nucleus and that the transported cargo is crucial for long-term plasticity. Indeed, two of the aforementioned synaptonuclear signaling proteins, Jacob and RNF10, are cargoes of the importin α1 isoform at the synapse [8,20], while another synaptonuclear signaling protein, NF-κB , is a cargo of importin α2 [26]. These studies suggest that different importin isoforms have distinct cargo and relay different signaling proteins to the nucleus [24].…”