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Membrane depolarization and calcium influx stimulate MEK and MAP kinase via activation of Ras
L B Rosen1, D D Ginty, M J Weber
1Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115.
Abstract:
A pathway by which calcium influx through voltage-sensitive calcium channels leads to mitogen-activated protein kinase (MAPK) activation has been characterized. In PC12 cells, membrane depolarization leading to calcium influx through L-type calcium channels activates the dual specificity MAPK kinase MEK1, which phosphorylates and activates MAPK. Calcium influx leads within 30 s to activation of the small guanine nucleotide-binding protein Ras. Moreover, activation of MAPK in response to calcium influx is inhibited by the dominant negative mutant RasAsn17, indicating that Ras activity is required for calcium signaling to MAPK. Ras is also activated by release of calcium from intracellular stores and by membrane depolarization of primary cortical neurons. The pleiotropic regulatory potential of both Ras and the MAPK pathway suggests that they may be central mediators of calcium signaling in the nervous system.
Insights
Calcium influx via voltage-sensitive channels activates mitogen-activated protein kinase (MAPK) signaling. This pathway involves Ras activation and is crucial for calcium
Area of Science:
- Neuroscience
- Cell Signaling
- Molecular Biology
Background:
- Calcium influx through voltage-sensitive channels is a key signaling event in neurons.
- Mitogen-activated protein kinase (MAPK) pathways regulate numerous cellular processes.
- The precise mechanisms linking calcium signaling to MAPK activation remain under investigation.
Purpose of the Study:
- To characterize the signaling pathway from calcium influx to MAPK activation.
- To determine the role of the small guanine nucleotide-binding protein Ras in this pathway.
- To investigate the involvement of intracellular calcium release and neuronal depolarization.
Main Methods:
- Utilized PC12 cells and primary cortical neurons.
- Employed membrane depolarization to induce calcium influx.
- Investigated the activation of MEK1 and MAPK.
- Assessed the role of Ras using a dominant-negative mutant (RasAsn17).
Main Results:
- Calcium influx through L-type channels activates MEK1, which activates MAPK.
- Calcium influx rapidly activates the small guanine nucleotide-binding protein Ras.
- Ras activity is essential for calcium-induced MAPK activation.
- Ras is also activated by intracellular calcium release and membrane depolarization in neurons.
Conclusions:
- A novel pathway linking calcium influx to MAPK activation via Ras has been elucidated.
- Ras and MAPK signaling are central mediators of calcium signaling in the nervous system.
- These findings provide insights into neuronal plasticity and function.