Control of Recruitment and Transcription-Activating Function of CBP Determines Gene Regulation by NMDA Receptors and L-Type Calcium Channels

Abstract

Recruitment of the coactivator CBP by signal-regulated transcription factors and stimulation of CBP activity are key regulatory events in the induction of gene transcription following Ca2+ flux through ligand- and/or voltage-gated ion channels in hippocampal neurons. The mode of Ca2+ entry (L-type Ca2+ channels versus NMDA receptors) differentially controls the CBP recruitment step to CREB, providing a molecular basis for the observed Ca2+ channel type-dependent differences in gene expression. In contrast, activation of CBP is triggered irrespective of the route of Ca2+ entry, as is activation of c-Jun, that recruits CBP independently of phosphorylation at major regulatory c-Jun phosphorylation sites, serines 63 and 73. This control of CBP recruitment and activation is likely relevant to other CBP-interacting transcription factors and represents a general mechanism through which Ca2+ signals associated with electrical activity may regulate the expression of many genes.

Hippocampal Focal Knockout of CBP Affects Specific Histone Modifications, Long-Term Potentiation, and Long-Term Memory

“…Together, these results suggest that although upstream signaling events appear normal, resulting in CREB phosphorylation, without CBP there is a failure to activate cfos expression. This uncoupling between phospho-CREB and CREB:CBP-mediated gene expression is similar to previous observations showing this dissociation in cell culture (Chawla et al, 1998;Hardingham et al, 1999).…”

“…In the late 1990s, two studies demonstrated that the phosphorylation of CREB could be uncoupled from CREBmediated gene expression (Chawla et al, 1998;Hardingham et al, 1999). Chawla et al (1998) proposed a model in which CREB:CBP-mediated gene expression requires two steps: The phosphorylation of CREB (resulting in the recruitment of CBP) and the phosphorylation of CBP for its activation.…”

“…However, whether these HATs can compensate at specific residues in the brain for a lack of CBP is unknown. We also examined whether CREB phosphorylation can be uncoupled from CREB:CBPmediated gene expression in vivo, as has been shown in cell culture (Chawla et al, 1998;Hardingham et al, 1999). Lastly, the effect of a homozygous deletion of Cbp on long-term potentiation (LTP) has never been examined.…”

The MAPK/ERK Cascade Targets Both Elk-1 and cAMP Response Element-Binding Protein to Control Long-Term Potentiation-Dependent Gene Expression in the Dentate GyrusIn Vivo

“…e, f, The level of p-CREB was greatly attenuated in SL327-treated rats compared with DMSO controls. Nordheim, 1996) and plays a key role in calcium-mediated gene transcription in cellular models of plasticity (Hardingham et al, 1999;Hu et al, 1999).…”

CALHM1 and its polymorphism P86L differentially control Ca2+ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β

“…CREB also plays a central role in memory formation (West et al ., 2001). The transcriptional activation of CREB is crucially dependent on phosphorylation of Ser133 by kinases such as Ca 2+ /calmodulin kinase (CaMK), ras/mitogen‐activated protein kinase (MAPK), ERK1/2 (Wu et al ., 2001), and protein kinases A and C (Hardingham et al ., 1999). Extracellular signal‐regulated kinases (ERKs) are key genes in activating survival pathways (Roskoski, 2012), and their transient activation plays an important role in memory‐related processes (Costa & Silva, 2002).…”