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The β subunits of voltage-gated Ca ²⁺ channels are known to be regulators of the channels' gating properties. Here we report a striking additional function of a β subunit. Screening of chicken cochlear and brain cDNA libraries identified β _4c , a short splice variant of the β ₄ subunit. Although β _4c occurs together with the longer isoforms β _4a or β _4b in the brain, eye, heart, and lung, the cochlea expresses exclusively β _4c . The association of β _4c with the Ca ²⁺ -channel α ₁ subunit has slight but significant effects on the kinetics of channel activation and inactivation. Yeast two-hybrid and biochemical assays revealed that β _4c interacts directly with the chromo shadow domain of chromobox protein 2/heterochromatin protein 1γ (CHCB2/HP1γ), a nuclear protein involved in gene silencing and transcriptional regulation. Coexpression of this protein specifically recruits β _4c to the nuclei of mammalian cells. Furthermore, β _4c but not β _4a dramatically attenuates the gene-silencing activity of chromobox protein 2/heterochromatin protein 1γ. The β _4c subunit is therefore a multifunctional protein that not only constitutes a portion of the Ca ²⁺ channel but also regulates gene transcription.

Voltage-gated Ca2+ channels (VGCCs) play a key role in neuronal signaling but can also contribute to cellular dysfunction and death under pathological conditions such as stroke and neurodegenerative diseases. We report that activation of N-methyl-d-aspartic acid receptors causes internalization and degradation of CaV1.2 channels, resulting in decreased Ca2+ entry and reduced toxicity. CaV1.2 internalization and degradation requires binding to phosphatidylinositol 3-phosphate 5-kinase (PIKfyve), a lipid kinase which generates phosphatidylinositol (3,5)-bisphosphate (PtdIns(3,5)P2) and regulates endosome and lysosome function. Sustained activation of glutamate receptors recruits PIKfyve to CaV1.2 channels, increases cellular levels of PtdIns(3,5)P2, and promotes targeting of CaV1.2 to lysosomes. Knockdown of PIKfyve prevents CaV1.2 degradation and increases neuronal susceptibility to excitotoxicity. These experiments identify a novel mechanism by which neurons are protected from excitotoxicity and provide a possible explanation for neuronal death in diseases caused by mutations that affect PtdIns(3,5)P2 regulation.

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 Ser10 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.