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The E1015K variant in the synprint region of the CaV2.1 channel alters channel function and is associated with different migraine phenotypes.

Authors: Condliffe, SB  Fratangeli, A  Munasinghe, NR  Saba, E  Passafaro, M  Montrasio, C  Ferrari, M  Rosa, P  Carrera, P 
Citation: Condliffe SB, etal., J Biol Chem. 2013 Nov 22;288(47):33873-83. doi: 10.1074/jbc.M113.497701. Epub 2013 Oct 9.
Pubmed: (View Article at PubMed) PMID:24108129
DOI: Full-text: DOI:10.1074/jbc.M113.497701

Mutations in the CACNA1A gene, which encodes the pore-forming alpha1A subunit of the CaV2.1 voltage-gated calcium channel, cause a number of human neurologic diseases including familial hemiplegic migraine. We have analyzed the functional impact of the E1015K amino acid substitution located in the "synprint" domain of the alpha1A subunit. This variant was identified in two families with hemiplegic migraine and in one patient with migraine with aura. The wild type (WT) and the E1015K forms of the GFP-tagged alpha1A subunit were expressed in cultured hippocampal neurons and HEK cells to understand the role of the variant in the transport activity and physiology of CaV2.1. The E1015K variant does not alter CaV2.1 protein expression, and its transport to the cell surface and synaptic terminals is similar to that observed for WT channels. Electrophysiological data demonstrated that E1015K channels have increased current density and significantly altered inactivation properties compared with WT. Furthermore, the SNARE proteins syntaxin 1A and SNAP-25 were unable to modulate voltage-dependent inactivation of E1015K channels. Overall, our findings describe a genetic variant in the synprint site of the CaV2.1 channel which is characterized by a gain-of-function and associated with both hemiplegic migraine and migraine with aura in patients.

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RGD Object Information
RGD ID: 10054426
Created: 2015-08-05
Species: All species
Last Modified: 2015-08-05
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.