Functional impact of a novel migraine mutation in the CaV2.1 channel
|dc.contributor.author||Munasinghe, Nehan Ruwantha|
|dc.identifier.citation||Munasinghe, N. R. (2012). Functional impact of a novel migraine mutation in the CaV2.1 channel (Thesis, Master of Science). University of Otago. Retrieved from http://hdl.handle.net/10523/2332||en|
|dc.description.abstract||The neuronal voltage gated Ca2+ channel CaV2.1, regulates neurotransmitter release. Recently, the E1015K polymorphism was identified in the SNARE interaction synprint site of CaV2.1 in migraine patients. In this study, we investigated whether synprint mutations alter CaV2.1 channel function as a molecular mechanism underlying migraine pathophysiology. Subsequently, we analysed whether SNARE interactions were modified. Channel function was characterised by whole cell patch clamping in HEK 293 cells transiently transfected with WT or E1015K CaV2.1. Results demonstrated that the E1015K polymorphism increased current density accompanied with a depolarising shift in voltage dependent inactivation and an increase in the inactivation rate. There was also a faster recovery from inactivation that could lead to increased Ca2+ influx under repeated stimulation. Additionally, little or no membrane expression of the isolated E1015K α1A subunit and similarity of WT and E1015K CaV2.1 membrane expression, suggests altered channel trafficking is not behind the elevated current density. Overall, results indicate that the E1015K polymorphism increases Ca2+ influx through changes in channel gating. This could lead to increased neurotransmitter release underlying migraine pathophysiology. Both SNARE proteins, SNAP 25 and syntaxin 1A downregulated E1015K CaV2.1 current density. Syntaxin 1A caused a possible decrease in WT current density accompanied with a hyperpolarising shift in inactivation. In contrast, SNAP 25 caused a possible decrease in WT current density and a significant decrease in E1015K current density with no changes in other channel kinetics. It was suggested that the E1015K polymorphism may alter SNAP 25 interaction. Overall, the presence of SNARE proteins may play a protective role to downregulate the elevated current density caused by the E1015K polymorphism.|
|dc.publisher||University of Otago|
|dc.rights||All items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.|
|dc.title||Functional impact of a novel migraine mutation in the CaV2.1 channel|
|thesis.degree.name||Master of Science|
|thesis.degree.grantor||University of Otago|
Files in this item
There are no files associated with this item.
This item is not available in full-text via OUR Archive.
If you are the author of this item, please contact us if you wish to discuss making the full text publicly available.