Proline Rich 7 (Prr7): An NMDA Receptor-Associated Synapto-Nuclear Protein Messenger in Control of c-Jun-Dependent Gene Transcription?

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The formation of long-term memories in the brain requires regulation of gene expression. In neurons different mechanisms have evolved to couple synaptic activity to gene transcription. Some of these signaling mechanisms need the transport of proteins from synapses to the nucleus. A particular rich source of synapto-nuclear protein messengers is the N-Methyl-D-Aspartate-receptor (NMDAR) complex. NMDAR are crucial mediators of neuronal plasticity and their number and localization at synapses is tightly regulated. Based on previous and recent unpublished work we propose to study the neuronal function of the transmembrane adaptor protein Prr7, which directly associates with NMDAR and appears to regulate their surface expression. Following enhanced synaptic activity Prr7 translocates to the nucleus and can bind the transcription factor c-Jun. With this application we want to prove the hypothesis that Prr7 can serve as an auxiliary subunit of NMDAR and that after proteolytical cleavage a fragment of the protein is actively transported to the nucleus, where it then regulates c-Jun-dependent gene transcription. We will analyze the genomic response to this novel signaling mechanism. Finally, we will test the idea that the nuclear import of cleaved Prr7 provides a read-out of the number of surface expressed and activated NMDAR.