Regulation of neuronal survival and CREB-dependent transcription by CaV1.2 L-type calcium channels
Abstract/Contents
- Abstract
- Electrical activity is a potent trophic factor that promotes the survival of many populations of neurons. L-type calcium channels (LTCs) are particularly effective at promoting survival of neurons during development, in part by activating transcription factors such as CREB. Mutation of the LTC CaV1.2 causes Timothy Syndrome (TS), a disorder characterized by cardiac arrhythmias, webbing of fingers and toes, and autism. The TS mutation leads to loss of voltage-dependent inactivation (VDI) of the channel. Although it is known that VDI is critical for the transition between the open and resting states of the channel, the role that channel inactivation plays in cell signaling and neuronal development is poorly understood. The work in this dissertation shows that the TS mutation impairs CaV1.2-dependent neuronal survival and prevents activation of the transcription factor CREB. By using TS channels that contain pore mutations that prevent Ca2+ flux, we found that the ability of TS channels to cause apoptosis is independent of Ca2+ flux through the channel. Conversely, a novel leucine to proline mutation at position 1368 restores VDI to TS channels and prevents TS-dependent apoptosis and inhibition of CREB. These findings support the idea that CaV1.2 conveys two signals that together regulate activity-dependent neuronal survival and activation of CREB: a signal that depends on the channel conformation and a signal that depends on calcium influx through the channel. These results provide new insights into the mechanisms by which the L-type calcium channels activate transcription and regulate neuronal survival during development.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2010 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Barreto-Chang, Odmara Liz |
|---|---|
| Associated with | Stanford University, Department of Neurosciences. |
| Primary advisor | Dolmetsch, Ricardo E |
| Thesis advisor | Dolmetsch, Ricardo E |
| Thesis advisor | Goodman, Miriam Beth |
| Thesis advisor | McConnell, Susan K |
| Thesis advisor | Scott, Matthew P |
| Advisor | Goodman, Miriam Beth |
| Advisor | McConnell, Susan K |
| Advisor | Scott, Matthew P |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Odmara Liz Barreto-Chang. |
|---|---|
| Note | Submitted to the Department of Neurosciences. |
| Thesis | Ph. D. Stanford University 2010 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2010 by Odmara Liz Barreto-Chang
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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