Caldendrin–Jacob: A Protein Liaison That Couples NMDA Receptor Signalling to the Nucleus

Abstract

NMDA (N-methyl-D-aspartate) receptors and calcium can exert multiple and very divergent effects within neuronal cells, thereby impacting opposing occurrences such as synaptic plasticity and neuronal degeneration. The neuronal Ca2+ sensor Caldendrin is a postsynaptic density component with high similarity to calmodulin. Jacob, a recently identified Caldendrin binding partner, is a novel protein abundantly expressed in limbic brain and cerebral cortex. Strictly depending upon activation of NMDA-type glutamate receptors, Jacob is recruited to neuronal nuclei, resulting in a rapid stripping of synaptic contacts and in a drastically altered morphology of the dendritic tree. Jacob's nuclear trafficking from distal dendrites crucially requires the classical Importin pathway. Caldendrin binds to Jacob's nuclear localization signal in a Ca2+-dependent manner, thereby controlling Jacob's extranuclear localization by competing with the binding of Importin-α to Jacob's nuclear localization signal. This competition requires sustained synapto-dendritic Ca2+ levels, which presumably cannot be achieved by activation of extrasynaptic NMDA receptors, but are confined to Ca2+ microdomains such as postsynaptic spines. Extrasynaptic NMDA receptors, as opposed to their synaptic counterparts, trigger the cAMP response element-binding protein (CREB) shut-off pathway, and cell death. We found that nuclear knockdown of Jacob prevents CREB shut-off after extrasynaptic NMDA receptor activation, whereas its nuclear overexpression induces CREB shut-off without NMDA receptor stimulation. Importantly, nuclear knockdown of Jacob attenuates NMDA-induced loss of synaptic contacts, and neuronal degeneration. This defines a novel mechanism of synapse-to-nucleus communication via a synaptic Ca2+-sensor protein, which links the activity of NMDA receptors to nuclear signalling events involved in modelling synapto-dendritic input and NMDA receptor–induced cellular degeneration.

Importin-mediated retrograde transport of CREB2 from distal processes to the nucleus in neurons

“…Consistent with this possibility, a recent study identified Jacob, a caldendrin binding partner, as a synaptically localized cargo of importin ␣1 that translocates to the nucleus after extrasynaptic NMDA receptor activation (10). In the present study, we show that the transcriptional repressor CREB2 is a synaptically localized cargo of importins.…”

“…A slower, more persistent mechanism of signaling to the nucleus involves the transport of soluble molecules from stimulated synapses to the nucleus (6,7). Recent studies have indicated that this type of transport may involve the active nuclear import pathway (8)(9)(10).…”

“…Importin ␤1 mediates facilitated translocation of this heterotrimeric complex across the nuclear pore. In neurons, importins may also function to carry signals from distal neuronal processes to the soma and into the nucleus (8)(9)(10)(11). This finding raises a critical question: what are the synaptically localized cargoes of importins that translocate to the nucleus to alter transcription during synaptic plasticity?…”

The Diversity of Calcium Sensor Proteins in the Regulation of Neuronal Function

“…Synaptic NMDAR mediated synpatodendritic [Ca 2þ ] i elevation induces caldendrin binding to Jacob, inhibiting nuclear trafficking and maintaining dendritic organization. This interaction represents a novel mechanism of synapse to nucleus communication and highlights the important roles of CaBP family members in the mammalian central nervous system (Dieterich et al 2008).…”

Dendritic mRNA Targeting of Jacob and N-Methyl-d-aspartate-induced Nuclear Translocation after Calpain-mediated Proteolysis

“…Particularly signaling from N-methyl-D-aspartate (NMDA) 3 type glutamate receptors to the nucleus has been implicated in synaptic plasticity, and some molecules have been identified that can translocate from synaptic and extrasynaptic sites to neuronal nuclei after NMDA receptor activation (3)(4)(5)(6)(7). In a recent study, we have identified Jacob, a protein that triggers long lasting changes in the cytoarchitecture of dendrites and the number of spine synapses in pyramidal neurons via coupling of NMDA receptor signaling to nuclear gene expression (6). Following activation of synaptic and extrasynaptic NMDA receptors, Jacob is recruited to neuronal nuclei, and this in turn results in a rapid stripping of synaptic contacts and in a drastically altered morphology of the dendritic tree (6).…”