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Channels (Austin). 2013 Mar-Apr;7(2):119-25. doi: 10.4161/chan.23895. Epub 2013 Mar 1.

Nuclear life of the voltage-gated Cacnb4 subunit and its role in gene transcription regulation.

Author information

1
Unité Inserm U836, Grenoble Institute of Neuroscience, La Tronche, France. michel.ronjat@ujf-grenoble.fr

Abstract

The pore-forming subunit of voltage-gated calcium channels is associated to auxiliary subunits among which the cytoplasmic β subunit. The different isoforms of this subunit control both the plasma membrane targeting and the biophysical properties of the channel moiety. In a recent study, we demonstrated that the Cacnb4 (β 4) isoform is at the center of a new signaling pathway that connects neuronal excitability and gene transcription. This mechanism relies on nuclear targeting of β 4 triggered by neuronal electrical stimulation. This re-localization of β 4 is promoted by its interaction with Ppp2r5d a regulatory subunit of PP2A in complex with PP2A itself. The formation, as well as the nuclear translocation, of the β 4/ Ppp2r5d/ PP2A complex is totally impaired by the premature R482X stops mutation of β 4 that has been previously associated with juvenile epilepsy. Taking as a case study the tyrosine hydroxylase gene that is strongly upregulated in brain of lethargic mice, deficient for β 4 expression, we deciphered the molecular steps presiding to this signaling pathway. Here we show that expression of wild-type β 4 in HEK293 cells results in the regulation of several genes, while expression of the mutated β 4 (β 1-481) produces a different set of gene regulation. Several genes regulated by β 4 in HEK293 cells were also regulated upon neuronal differentiation of NG108-15 cells that induces nuclear translocation of β 4 suggesting a link between β 4 nuclear targeting and gene regulation.

KEYWORDS:

HP1γ; gene transcription regulation; phosphatase 2A; thyroid receptor alpha; tyrosine hydroxylase; voltage-gated calcium channel; β4 subunit

PMID:
23511121
PMCID:
PMC3667881
DOI:
10.4161/chan.23895
[Indexed for MEDLINE]
Free PMC Article
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