Neuronal calcium activates a Rap1 and B-Raf signaling pathway via the cyclic adenosine monophosphate-dependent protein kinase

Savraj S. Grewal, Angela Horgan, Randall D. York, Ginger S. Withers, Gary Banker, Philip Stork

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

Activity-dependent regulation of neuronal events such as cell survival and synaptic plasticity is controlled by increases in neuronal calcium levels. These actions often involve stimulation of intracellular kinase signaling pathways. For example, the mitogen-activated protein kinase, or extracellular signal-regulated kinase (ERK), signaling cascade has increasingly been shown to be important for the induction of gene expression and long term potentiation. However, the mechanisms leading to ERK activation by neuronal calcium are still unclear. In the present study, we describe a protein kinase A (PKA)-dependent signaling pathway that may link neuronal calcium influx to ERKs via the small G-protein, Rap1, and the neuronal Raf isoform, B-Raf. Thus, in PC12 cells, depolarization-mediated calcium influx led to the activation of B-Raf, but not Raf-1, via PKA. Furthermore, depolarization also induced the PKA-dependent stimulation of Rap1 and led to the formation of a Rap1/B-Raf signaling complex. In contrast, depolarization did not lead to the association of Ras with B-Raf. The major action of PKA- dependent Rap1/B-Raf signaling in neuronal cells is the activation of ERKs. Thus, we further show that, in both PC12 cells and hippocampal neurons, depolarization-induced calcium influx stimulates ERK activity in a PKA- dependent manner. Given the fact that both Rap1 and B-Raf are highly expressed in the central nervous system, we suggest that this signaling pathway may regulate a number of activity-dependent neuronal functions.

Original languageEnglish (US)
Pages (from-to)3722-3728
Number of pages7
JournalJournal of Biological Chemistry
Volume275
Issue number5
DOIs
StatePublished - Feb 4 2000

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Cyclic AMP-Dependent Protein Kinases
Depolarization
Calcium
Extracellular Signal-Regulated MAP Kinases
PC12 Cells
Chemical activation
Neuronal Plasticity
Monomeric GTP-Binding Proteins
Long-Term Potentiation
Mitogen-Activated Protein Kinases
Neurology
Cell Survival
Protein Isoforms
Gene expression
Phosphotransferases
Central Nervous System
Neurons
Plasticity
Gene Expression
Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Neuronal calcium activates a Rap1 and B-Raf signaling pathway via the cyclic adenosine monophosphate-dependent protein kinase. / Grewal, Savraj S.; Horgan, Angela; York, Randall D.; Withers, Ginger S.; Banker, Gary; Stork, Philip.

In: Journal of Biological Chemistry, Vol. 275, No. 5, 04.02.2000, p. 3722-3728.

Research output: Contribution to journalArticle

Grewal, Savraj S. ; Horgan, Angela ; York, Randall D. ; Withers, Ginger S. ; Banker, Gary ; Stork, Philip. / Neuronal calcium activates a Rap1 and B-Raf signaling pathway via the cyclic adenosine monophosphate-dependent protein kinase. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 5. pp. 3722-3728.
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