Figure 4. Model for ERK-mediated regulation of histone acetylation and gene transcription.

Activation of the NMDA subtype of glutamate receptors (NMDARs) and voltage-gated Ca++ channels leads to influx of Ca++ and activation of the ras-MEK-ERK signaling cascade in adult neurons. This leads to activation of CREB-mediated transcription via intermediary actions of RSK2 or the Mitogen Stimulated Kinase, MSK. A downstream target of these kinases, CREB, is postulated to facilitate transcription through interaction with CREB-binding protein (CBP) and acetylation of histones. Additional pathways for regulating chromatin structure in memory include metabotropic glutamate receptor (mGluR) and NMDAR activation of Protein Kinase M zeta (PKMzeta) and downstream targeting of NFkappaB signaling in the nucleus. ERK MAPK signaling can also activate this pathway as an ancillary mechanism for chromatin regulation. Targets of this pathway include the transcription factors c-rel and Elk-1, which can regulate the expression of the MAPK Phosphatase MKP-3, which represents a likely site of negative feedback control of the pathway. See text and (Lubin and Sweatt, 2007) for additional discussion.