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Publication : Cacnb4 directly couples electrical activity to gene expression, a process defective in juvenile epilepsy.

First Author  Tadmouri A Year  2012
Journal  EMBO J Volume  31
Issue  18 Pages  3730-44
PubMed ID  22892567 Mgi Jnum  J:188568
Mgi Id  MGI:5441119 Doi  10.1038/emboj.2012.226
Citation  Tadmouri A, et al. (2012) Cacnb4 directly couples electrical activity to gene expression, a process defective in juvenile epilepsy. EMBO J 31(18):3730-44
abstractText  Calcium current through voltage-gated calcium channels (VGCC) controls gene expression. Here, we describe a novel signalling pathway in which the VGCC Cacnb4 subunit directly couples neuronal excitability to transcription. Electrical activity induces Cacnb4 association to Ppp2r5d, a regulatory subunit of PP2A phosphatase, followed by (i) nuclear translocation of Cacnb4/Ppp2r5d/PP2A, (ii) association with the tyrosine hydroxylase (TH) gene promoter through the nuclear transcription factor thyroid hormone receptor alpha (TRalpha), and (iii) histone binding through association of Cacnb4 with HP1gamma concomitantly with Ser(10) histone H3 dephosphorylation by PP2A. This signalling cascade leads to TH gene repression by Cacnb4 and is controlled by the state of interaction between the SH3 and guanylate kinase (GK) modules of Cacnb4. The human R482X CACNB4 mutation, responsible for a form of juvenile myoclonic epilepsy, prevents association with Ppp2r5 and nuclear targeting of the complex by altering Cacnb4 conformation. These findings demonstrate that an intact VGCC subunit acts as a repressor recruiting platform to control neuronal gene expression.
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