From calcium channels to autism : effects of the Timothy Syndrome mutation in CaV1.2 on neuronal development
Abstract/Contents
- Abstract
- L-type voltage-gated calcium channels (LTCs) play a key role in neuronal development by activating signalling pathways that regulate neuronal gene expression and morphology. A point mutation in the LTC CaV1.2, which blocks voltage-dependent inactivation (VDI), causes autism in Timothy Syndrome (TS) patients. While it is known how VDI influences the current through LTCs, it is not known how alterations in VDI affect the signaling function of CaV1.2 in neurons and ultimately cause developmental defects that lead to autism. Here I show that expression of CaV1.2 channels containing the TS mutation (TS-CaV1.2) inhibits CRE-dependent transcription and causes dendrite retraction and reduced dendrite branching in cortical neurons. I found that expression of TS-CaV1.2 leads to increased calcium influx in neurons and that this increase in intracellular calcium concentrations was in part responsible for the ability of TS-CaV1.2 channels to inhibit CREB. Surprisingly, however, I found that TS-CaV1.2 causes dendritic retraction independently of Ca2+ influx through the channel suggesting that the voltage-dependent conformational changes associated with VDI play an important and unexpected role in CaV1.2 signalling. In addition, I found that TS-CaV1.2 causes dendrite retraction by activating the RhoA signalling pathway. I found that changes in the interaction of the small GTP-binding protein Gem with the channel beta subunit play a critical role in mediating the activation of RhoA by TS-CaV1.2. These results provide new insight into how LTCs are coupled to cytoskeletal signalling pathways in neurons and shed light on the molecular mechanisms underlying the generation of TS and other Autism Spectrum Disorders.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Copyright date | 2010 |
| Publication date | 2009, c2010; 2009 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Krey, Jocelyn Friedman | |
|---|---|---|
| Associated with | Stanford University, Neurosciences Program. | |
| Primary advisor | Dolmetsch, Ricardo E | |
| Thesis advisor | Dolmetsch, Ricardo E | |
| Thesis advisor | Garner, Craig | |
| Thesis advisor | Lewis, Richard (Richard Sheridan) | |
| Thesis advisor | Luo, Liqun, 1966- | |
| Advisor | Garner, Craig | |
| Advisor | Lewis, Richard (Richard Sheridan) | |
| Advisor | Luo, Liqun, 1966- |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Jocelyn Friedman Krey. |
|---|---|
| Note | Submitted to the Neurosciences Program. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2010. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2010 by Jocelyn Friedman Krey
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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