title: Nuclear life of the voltage-gated Cacnb4 subunit and its role in gene transcription regulation.
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.
authors.affiliation: Unité Inserm U836, Grenoble Institute of Neuroscience, La Tronche, France. michel.ronjat@ujf-grenoble.fr
authors.forename: Michel
authors.initials: M
authors.lastname: Ronjat
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kiyonaka
authors.forename: Maud
authors.initials: M
authors.lastname: Barbado
authors.forename: Michel
authors.initials: M
authors.lastname: De Waard
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C107598:CACNB4 protein, human; D015220:Calcium Channels; D021122:Protein Subunits; D014446:Tyrosine 3-Monooxygenase; D054648:Protein Phosphatase 2
keywords: HP1γ; gene transcription regulation; phosphatase 2A; thyroid receptor alpha; tyrosine hydroxylase; voltage-gated calcium channel; β4 subunit