New Insights in CaVβ Subunits: Role in the Regulation of Gene Expression and Cellular Homeostasis

Abstract

The voltage-gated calcium channels (CaVs or VGCCs) are fundamental regulators of intracellular calcium homeostasis. When electrical activity induces their activation, the influx of calcium that they mediate or their interaction with intracellular players leads to changes in intracellular Ca2+ levels which regulate many processes such as contraction, secretion and gene expression, depending on the cell type. The essential component of the pore channel is the CaVα1 subunit. However, the fine-tuning of Ca2+-dependent signals is guaranteed by the modulatory role of the auxiliary subunits β, α2δ, and γ of the CaVs. In particular, four different CaVβ proteins (CaVβ1, CaVβ2, CaVβ3, and CaVβ4) are encoded by four different genes in mammalians, each of them displaying several splice variants. Some of these isoforms have been described in regulating CaVα1 docking and stability at the membrane and controlling the channel complex’s conformational changes. In addition, emerging evidences have highlighted other properties of the CaVβ subunits, independently of α1 and non-correlated to its channel or voltage sensing functions. This review summarizes the recent findings reporting novel roles of the auxiliary CaVβ subunits and in particular their direct or indirect implication in regulating gene expression in different cellular contexts.

Nanoscale architecture and dynamics of CaV1.3 channel clusters in cardiac myocytes revealed by single channel nanoscopy

“…The pore-forming subunit α 1D was tagged at the N-terminus preserving channel voltage-gating, while the C-terminus is crucial for regulatory functions that may be perturbed by fusion-tagging. In addition, we considered that alternative tagging of the accessory β-subunit (Conrad et al, 2021; Del Villar et al, 2021; Liu et al, 2020) was unsuitable for our study since Ca V β can bind other Ca 2+ channel isoforms and performs intracellular functions (Vergnol et al, 2022). We developed independent and synergistic cluster analysis workflows on hiPSC-aCM expressing tagged Ca V 1.3 proteins.…”

Cavβ3 Contributes to the Maintenance of the Blood-Brain Barrier and Alleviates Symptoms of Experimental Autoimmune Encephalomyelitis

“…20,21 The Cavβ subunits Cavβ1, Cavβ3, and Cavβ4 translocate to the nucleus where they influence gene expression. [22][23][24][25][26] When the electrical activity of innervated adult mouse muscle cells is impaired, the expression of a splice variant of Cavβ1 (Cavβ1e) is upregulated to limit the loss of muscle mass via GDF5 (growth differentiation factor 5). Overexpression of Cavβ1e in aged mice activates the GDF5 signaling pathway and counteracts age-related muscle mass loss.…”

“…Overexpression of Cavβ1e in aged mice activates the GDF5 signaling pathway and counteracts age-related muscle mass loss. 25,26 In cardiomyocytes, a fraction of Cavβ2 translocates to the nucleus and regulates calpain-dependent hypertrophic signaling pathways. 27 Cavβ1 has been identified in T cells in the absence of functional Cav currents and may play a role in the regulation of T-cell proliferation and apoptosis.…”