title: The juvenile myoclonic epilepsy mutant of the calcium channel β(4) subunit displays normal nuclear targeting in nerve and muscle cells.
abstract: Voltage-gated calcium channels regulate gene expression by controlling calcium entry through the plasma membrane and by direct interactions of channel fragments and auxiliary β subunits with promoters and the epigenetic machinery in the nucleus. Mutations of the calcium channel β(4) subunit gene (CACNB4) cause juvenile myoclonic epilepsy in humans and ataxia and epileptic seizures in mice. Recently a model has been proposed according to which failed nuclear translocation of the truncated β(4) subunit R482X mutation resulted in altered transcriptional regulation and consequently in neurological disease. Here we examined the nuclear targeting properties of the truncated β(4b(1–481)) subunit in tsA-201 cells, skeletal myotubes, and in hippocampal neurons. Contrary to expectation, nuclear targeting of β(4b(1–481)) was not reduced compared with full-length β(4b) in any one of the three cell systems. These findings oppose an essential role of the β(4) distal C-terminus in nuclear targeting and challenge the idea that the nuclear function of calcium channel β(4) subunits is critically involved in the etiology of epilepsy and ataxia in patients and mouse models with mutations in the CACNB4 gene.
authors.forename: Solmaz
authors.initials: S
authors.lastname: Etemad
authors.forename: Marta
authors.initials: M
authors.lastname: Campiglio
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Obermair
authors.forename: Bernhard E
authors.initials: BE
authors.lastname: Flucher
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D032342:Muscle Cells / Q000378:metabolism* / Q000473:pathology; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D021122:Protein Subunits / Q000235:genetics*; D021381:Protein Transport
chemical_list: C107598:CACNB4 protein, human; C491530:Cacnb4 protein, mouse; D015220:Calcium Channels; D050505:Mutant Proteins; D021122:Protein Subunits