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).
