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

Abstract

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 (TRa), and (iii) histone binding through association of Cacnb4 with HP1c 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.

B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability

“…Moreover, PKA-activated PP2A-B56δ-dependent dephosphorylation of another DARPP-32 phosphorylation site (Ser-97) induces nuclear import -mediating dopamine-dependent epigenetic functions (25) -and lack of nuclear PP2A-B56δ targeting has been associated with juvenile myoclonic epilepsy (30). There is also evidence that PP2A-B56δ regulates both expression (30) and activity (31) of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. Which of these candidate substrates will eventually be of pathologic relevance in our ID patients remains to be further determined in appropriate cellular and animal models.…”

“…B56δ has several sites for PKA phosphorylation that activate PP2A-B56δ phosphatase activity (24,29). Moreover, PKA-activated PP2A-B56δ-dependent dephosphorylation of another DARPP-32 phosphorylation site (Ser-97) induces nuclear import -mediating dopamine-dependent epigenetic functions (25) -and lack of nuclear PP2A-B56δ targeting has been associated with juvenile myoclonic epilepsy (30). There is also evidence that PP2A-B56δ regulates both expression (30) and activity (31) of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis.…”

Generation of a neuro-specific microarray reveals novel differentially expressed noncoding RNAs in mouse models for neurodegenerative diseases

“…For proof of principle, we investigated ncRNA expression upon changes in calcium channel (Ca V ) activity, which has been implicated in a variety of neurological disorders such as psychiatric disorders (O'Roak et al 2012; CrossDisorder Group of the Psychiatric Genomics Consortium 2013) or Parkinson's disease, respectively (Sulzer and Surmeier 2013). Thereby, we analyzed differential expression of ncRNAs in knockout mouse models for one of the two brain L-type calcium channels (Ca v 1.3) being implicated in Parkinson's disease (Sulzer and Surmeier 2013) and in lethargic mice, which harbor a nonsense mutation in the gene encoding for the auxiliary voltage-dependent Ca 2+ channel β 4 subunit (Cacnb4), previously described as a model for idiopathic epilepsy and ataxia (Burgess et al 1997;Tadmouri et al 2012). In addition, we applied the customized neuroncRNA microarray to a well-characterized triple-transgenic mouse model (3xTG) for Alzheimer's disease (Oddo et al 2003).…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…Several studies demonstrated targeting of b 4 subunits into the nucleus, suggesting a direct function in activity-dependent gene regulation (Colecraft et al, 2002;Hibino et al, 2003;Subramanyam et al, 2009;Tadmouri et al, 2012). Isoform-specific functions of b 4 splice variants were recently observed in neurons (Etemad et al, 2014).…”