NEURONAL SIGNAL TRANSDUCTION: REGULATION OF NUCLEAR SIGNALING
In addition to short-term modulation of individual synapses, increased excitatory neuron firing can lead to changes in gene expression through several mechanisms.In particular, increased calcium levels arising from NMDAR activation and BDNF binding to TrkB can activate calcium calmodulin kinase IV (CaMKIV), leading to phosphorylation and activation of the cAMP response element-binding protein (CREB) transcription factor, which recruits critical transcriptional elements such as CREB-binding protein (CBP), TATA-binding protein (TBP), and RNA polymerase II (POL2) to genes with cAMP response elements (CRE), ultimately leading to transcription of factors related to synaptic plasticity.
CREB can also be phosphorylated by cAMP-dependent activation of protein kinase A (PKA), providing a mechanism for modulation of gene transcription by G-protein coupled receptors such as dopamine 1-like receptors (D1 receptor). Activation of growth factor receptors such as TrkB can also result in Ras-dependent activation of the mitogen activated protein kinase (MAPK) pathway, ultimately leading to phosphorylation of CREB by a MAPK/ribosomal s6 kinase (RSK) dimer. In addition to CREB, many other transcription factors can be activated to influence neuronal gene expression including c-Fos, c-Jun, nuclear factor kappa B (NF-κB), and steroid hormone receptors such as the glucocorticoid receptor (GR; see Fig. 1.38).