The Structural Basis For Integrating Synaptic Activity In The Nucleus

From what is outlined above, it can already be deduced that a high degree of convergence and synergy must exist between synapse-to-nucleus signaling pathways. The integration of many different upstream signaling events into a coordinated nuclear response is a major challenge for synapse-to-nucleus communication. Thus, many divergent intracellular signaling cascades can regulate the same nuclear target providing a high degree of fine-tuning that might be of importance in controlling activity-dependent gene transcription. One prominent example for the integration of different Ca2+ signals that control gene transcription is the brain-derived neurotrophic factor (BDNF) promoter III, which requires induction of three Ca2+-responsive elements (Figure 22.3). The exon-III containing splice isoforms are particularly sensitive to regulation by synaptic activity and it was shown that a region 170bp upstream of the exon III initiation site is responsible for the activity-dependent induction of BDNF mRNA32,33. Within this region three Ca2+-responsive elements were identified, one of which constituting a Ca2+/cAMP response element that is bound to CREB32,33. Phosphorylation of CREB is necessary but not sufficient for the expression of exon III32,33. Accordingly, BDNF exon III expression is selectively activated by Ca2+ influx but not by other stimuli that enhance the phosphorylation of CREB, like for instance, elevated cAMP levels34. The two other Ca2+-responsive elements were recently characterized as binding sites for MeCP235-37 and a novel Ca2+-responsive transcription factor termed CaRF34. MeCP2 functions as a transcriptional repressor of BDNF gene expression whereas CaRF is a transcriptional activator. Membrane depolarization triggers a Ca2+-dependent phosphorylation and subsequent release of MeCP2 from the BDNF exon III promoter thereby facilitating transcription. The transcriptional activity of CaRF also requires elevated Ca2+ levels but the mechanism of Ca2+ activation is not yet known. Interestingly, coordination of the activity of all three transcription factors bound at the Ca2+-responsive elements within the BDNF exon III promoter seems to be required for the expression of BDNF exon III containing transcripts in cortical primary cultures. Thus, although distinct Ca2+-signaling mechanisms for CaRF, CREB, and MeCP2 have not been identified yet, it is tempting to speculate that differences in Ca2+ regulation for these proteins might determine specificity for gene induction in response to Ca2+ influx.

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