Molecules At The Synapse In Control Of Synaptonuclear Signaling

Several studies in recent years have shown that it is not the increase of intracellular Ca2+ levels per se that leads to activation of gene expression and that it is therefore an open question of what type of Ca2+ signal is needed for activity-dependent transcriptional regulation. The local activation of signaling pathways to the nucleus by plasma membrane Ca2+ channels requires the concerted action of many proteins that are supposed to be present in highly organized macromolecular complexes close to the synaptic membrane (Figure 22.2). Most models of synapto-nuclear signaling implicitly assume that upon synaptic release of glutamate Ca2+ influx via NMDARs and L-type Ca2+ channels is restricted to the microcompartment of dendritic spine synapses (Figure 22.2). These synaptic Ca2+ signals are subsequently thought to be transduced to the nucleus via activation of the CaMKII, Ras/extracellular signal-regulated protein kinase (ERK), and stress-activated-protein-kinase (SAPK) pathways5,7. Interestingly, for all these pathways a potential role in coupling synaptic signals to nuclear CREB phosphorylation has been demonstrated5,7.

Figure 22.2. Molecules at the Synapse in Control of Synapto-Nuclear Signaling. Synaptic Ca2+ signals are thought to be transduced to the nucleus via activation of the CaMKII, Ras/ERK, SAPK pathways, and CREB phosphorylation. The Ca2+-dependent signaling initiated by the activation of NMDA receptors and L-type Ca2+ channels is modulated by Ca2+-independent mechanisms mediated by EphB receptors and mGluR5, and requires the concerted action of many proteins that are highly organized in macromolecular complexes at the synaptic membrane.

Figure 22.2. Molecules at the Synapse in Control of Synapto-Nuclear Signaling. Synaptic Ca2+ signals are thought to be transduced to the nucleus via activation of the CaMKII, Ras/ERK, SAPK pathways, and CREB phosphorylation. The Ca2+-dependent signaling initiated by the activation of NMDA receptors and L-type Ca2+ channels is modulated by Ca2+-independent mechanisms mediated by EphB receptors and mGluR5, and requires the concerted action of many proteins that are highly organized in macromolecular complexes at the synaptic membrane.

Specificity for the coupling of synaptic activity to nuclear gene expression seems to be brought about by the subcellular targeting and localization of the signaling molecules involved. It has been suggested that the activation of ERK1/2 by a spatially restricted pool of Ca2+ is likely due to the association of ERK1/2 and their activator molecules with the NMDA receptor complex (Figure 22.2). Along these lines it was speculated that the NMDA-receptor activated Ca2+ influx represents the most sensitive Ca2+ pathway for synapse-to-nucleus signaling26. Of particular interest in this regard is the finding that Ca2+ influx through synaptic NMDARs and L-type Ca2+ channels as well as activity of their downstream effectors can be modulated by receptor tyrosine kinases and G-protein coupled receptors27-29. Moreover, the tyrosine kinase activity of EphB receptors as well as the ligand-induced activation of the metabotropic glutamate receptor 5 (mGluR5)

also modulate NMDA-receptor controlled gene expression27,28 (Figure 22.2). In both cases the ligand-receptor interactions induce a synergistic increase of ERK phosphorylation that is independent of the conventional Ca2+ signaling derived from NMDA receptors (Ca2+ influx) and mGluR5 (intracellular Ca2+ release). Furthermore, the phosphorylation of ERK and CREB requires the interaction of adaptor proteins or the EphB4 with the NMDA-receptor complex27-29. Thus, Ca2+-independent NMDA-receptor coupled signaling pathways to ERK exist that are not directly triggered by synaptic activity as a read-out of Ca2+ signaling, and that will add another level of regulation to synapse-to-nucleus communication. Furthermore, an intriguing different outcome on CREB phosphorylation on Ser-133 was reported after stimulation of synaptic and extrasynaptic NMDA receptors. Whereas activation of synaptic NMDA receptors results in enhanced nuclear CREB phosphorylation on Ser-133, the opposite was found after stimulation of extrasynaptic NMDA receptors (Figure 22.2)30. In conclusion, it can be hypothesized that the spatio-temporal aspect of Ca2+ signaling and thereby the localization of the Ca2+ entry or release channel, might to a large extent determine the type of regulatory event triggered in the nucleus.

Additional specificity with regard to synaptic input is probably brought about by the spatial or temporal features of the signal that is generated within a neuron in response to synaptic activity. Thus, synaptic stimulation protocols that strengthen synaptic transmission often generate high frequency Ca2+ transients that accumulate to produce relatively high elevations of intracellular Ca2+ in vitro31. By contrast, protocols that weaken synaptic connections often evoke low-frequency Ca2+ transients that moderately elevate intracellular Ca2+ 31. The precise underlying molecular mechanisms as well as their spatio-temporal dynamics are, however, largely unclear.

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