Sending signals from the synapse to the nucleus: Possible roles for CaMK, Ras/ERK, and SAPK pathways in the regulation of synaptic plasticity and neuronal growth

Abstract

The ability to learn and form memories depends on specific patterns of synaptic activity and is in part transcription dependent. However, the signal transduction pathways that connect signals generated at synapses with transcriptional responses in the nucleus are not well understood. In the present report, we discuss three signal transduction pathways: the Ca(2+)/calmodulin-dependent kinase (CaMK) pathway, the Ras/ERK pathway, and the SAPK pathways that might function to couple synaptic activity to long-term adaptive responses, in part through the regulation of new gene expression. Evidence suggests that these pathways become activated in response to stimuli that regulate synaptic function such as the influx of extracellular Ca(2+) and certain neurotrophin growth factors such as brain-derived neurotrophic factor. Once activated, the CaMK, Ras/ERK, and SAPK pathways lead to the phosphorylation and activation of transcription factors in the nucleus such as the cyclic AMP response element binding protein (CREB). Genes regulated by CREB or other transcription factor targets of the CaMK, Ras/ERK, and SAPK pathways could mediate important adaptive responses to changes in synaptic activity such as changes in synaptic strength and the regulation of neuronal survival and death.

Sustained Extracellular Signal-Regulated Kinase 1/2 Phosphorylation in Neonate 6-Hydroxydopamine-Lesioned Rats after Repeated D1-Dopamine Receptor Agonist Administration: Implications for NMDA Receptor Involvement

“…A well characterized nuclear target for ERK action is the transcription factor CREB (Bourtchuladze et al, 1994;Yin et al, 1994), which is thought to play a central role in long-term plastic changes in brain by controlling the transcriptional expression of several genes (for review, see Curtis and Finkbeiner, 1999). In the present study, immunostaining for phospho-CREB was measured initially as a functional endpoint for sustained ERK activation in MPC.…”

Thenob2mouse, a null mutation inCacna1f: Anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses

“…In these mutants the abnormal calcium signaling could involve processes other than neurotransmitter release (Ghosh & Greenberg, 1995). For example, calcium influx can activate intracellular pathways, which can act locally at the synapse or mediate changes in nuclear gene transcription (Rosen et al, 1994;Ghosh & Greenberg, 1995;Curtis & Finkbeiner, 1999), processes that have the potential to alter cell surface molecules that may be critical to normal synapse formation. In vitro studies have presented a possible link between VDCCs and photoreceptor development in which VDCC blockade inhibits process outgrowth, varicosity formation, and vesicle protein synthesis in developing rods (Zhang & Townes-Anderson, 2002;NachmanClewner et al, 1999).…”

Role for D-Serine within the Ventral Tegmental Area in the Development of Cocaine's Sensitization

“…Calcium signaling pathways play a pivotal role in synaptic plasticity and memory formation (Dubnau and Tully, 1998;Ho et al, 2000), as well as CaMKII (Silva et al, 1992). CaMKII functions as a potent stimulator of calcium-dependent gene expression, and it activates several transcription factors such as CREB, which is phosphorylated on the regulatory Ser133 residue (Matthews et al, 1994;Curtis and Finkbeiner, 1999). CREB activation in the VTA is directly involved in sensitization and regulates tyrosine hydroxylase (TH) transcription (Lim et al, 2000).…”