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

• Published in: The EMBO journal Vol. 31; no. 18; pp. 3730 - 3744
• Main Authors: Tadmouri, Abir, Kiyonaka, Shigeki, Barbado, Maud, Rousset, Matthieu, Fablet, Katell, Sawamura, Seishiro, Bahembera, Eloi, Pernet-Gallay, Karin, Arnoult, Christophe, Miki, Takafumi, Sadoul, Karin, Gory-Faure, Sylvie, Lambrecht, Caroline, Lesage, Florian, Akiyama, Satoshi, Khochbin, Saadi, Baulande, Sylvain, Janssens, Veerle, Andrieux, Annie, Dolmetsch, Ricardo, Ronjat, Michel, Mori, Yasuo, De Waard, Michel
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 12-09-2012; Nature Publishing Group UK; Blackwell Publishing Ltd; EMBO Press; Nature Publishing Group
• Subjects: Active Transport, Cell Nucleus; Animals; Biophysics; Biophysics - methods; Calcium channels; Calcium Channels - biosynthesis; Calcium Channels - genetics; Calcium Channels - metabolism; Electrophysiology - methods; EMBO09; EMBO27; EMBO37; Epilepsies, Myoclonic - metabolism; Epilepsy; Gene expression; Gene Expression Regulation; gene regulation; Green Fluorescent Proteins - metabolism; HEK293 Cells; Histones - metabolism; HP1γ; Humans; Kinases; Life Sciences; Mice; Molecular biology; Mutation; Neurons and Cognition; phosphatase 2A; Protein Phosphatase 2 - metabolism; Signal Transduction; Thyroid; Thyroid Hormone Receptors alpha - metabolism; thyroid receptor alpha; Transcription, Genetic; Translocation; β4 subunit; phosphatase 2A; β; subunit; HP1γ; gene regulation; thyroid receptor alpha; β4 subunit; Gene regulation
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2012.226

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 (TRα), and (iii) histone binding through association of Cacnb4 with HP1γ concomitantly with Ser
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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.
CacnB4, an auxiliary subunit of the voltage‐gated calcium channels, plays an additional direct role in transcriptional repression, associating with PP2A phosphatase to alter histone modifications at a TRα‐bound promoter.