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

Abstract

Mutations in the CACNA1A gene, which encodes the pore-forming α1A 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 α1A 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 α1A 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.

• Authors: Steven B Condliffe, Alessandra Fratangeli, Nehan R Munasinghe, Elena Saba, Maria Passafaro, Cristina Montrasio, Maurizio Ferrari, Patrizia Rosa, Paola Carrera
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 47 Pg. 33873-33883 (Nov 22 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 24108129 (Publication Type: Journal Article)

Chemical References

• Calcium Channels, N-Type
• Nerve Tissue Proteins
• SNAP25 protein, human
• STX1A protein, human
• Snap25 protein, rat
• Stx1a protein, rat
• Synaptosomal-Associated Protein 25
• Syntaxin 1
• voltage-dependent calcium channel (P-Q type)

Topics

• Adolescent
• Adult
• Amino Acid Substitution
• Animals
• Calcium Channels, N-Type (genetics, metabolism)
• Child
• Female
• HEK293 Cells
• Hippocampus (metabolism, pathology)
• Humans
• Ion Transport (genetics)
• Male
• Middle Aged
• Migraine with Aura (genetics, metabolism, pathology)
• Mutation, Missense
• Nerve Tissue Proteins (genetics, metabolism)
• Presynaptic Terminals (metabolism, pathology)
• Rabbits
• Rats
• Synaptosomal-Associated Protein 25 (genetics, metabolism)
• Syntaxin 1 (genetics, metabolism)