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

The pore-forming subunit of voltage-gated calcium channels is associated to auxiliary subunits among which the cytoplasmic beta 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 (beta(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 beta(4) triggered by neuronal electrical stimulation. This re-localization of beta(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 beta(4)/Ppp2r5d/PP2A complex is totally impaired by the premature R482X stops mutation of beta(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 beta(4) expression, we deciphered the molecular steps presiding to this signaling pathway. Here we show that expression of wild-type beta(4) in HEK293 cells results in the regulation of several genes, while expression of the mutated beta(4) (beta(1-481)) produces a different set of gene regulation. Several genes regulated by beta(4) in HEK293 cells were also regulated upon neuronal differentiation of NG108-15 cells that induces nuclear translocation of beta(4) suggesting a link between beta(4) nuclear targeting and gene regulation.