Cacnb4 directly couples electrical activity to gene expression, a process defective in juvenile epilepsy.
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(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.
Unité Inserm U, Grenoble Institute of Neuroscience, Université Joseph Fourier, La Tronche, France.
Abir
A
Tadmouri
Shigeki
S
Kiyonaka
Maud
M
Barbado
Matthieu
M
Rousset
Katell
K
Fablet
Seishiro
S
Sawamura
Eloi
E
Bahembera
Karin
K
Pernet-Gallay
Christophe
C
Arnoult
Takafumi
T
Miki
Karin
K
Sadoul
Sylvie
S
Gory-Faure
Caroline
C
Lambrecht
Florian
F
Lesage
Satoshi
S
Akiyama
Saadi
S
Khochbin
Sylvain
S
Baulande
Veerle
V
Janssens
Annie
A
Andrieux
Ricardo
R
Dolmetsch
Michel
M
Ronjat
Yasuo
Y
Mori
Michel
M
De Waard
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001703:Biophysics / Q000379:methods; D015220:Calcium Channels / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D004594:Electrophysiology / Q000379:methods; D004831:Epilepsies, Myoclonic / Q000378:metabolism*; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D015398:Signal Transduction; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism; D014158:Transcription, Genetic
C107598:CACNB4 protein, human; C491530:Cacnb4 protein, mouse; D015220:Calcium Channels; D006657:Histones; C525691:PPP2R5D protein, human; D037021:Thyroid Hormone Receptors alpha; D049452:Green Fluorescent Proteins; D054648:Protein Phosphatase 2