Down-regulation of the Wnt/β-catenin signaling pathway by Cacnb4

Abstract

The cytoplasmic β4-subunit of the voltage-gated calcium channels has been shown be involved in the regulation of gene transcription. This subunit interacts with the transcription factor TCF4 and inhibits the Wnt/β-catenin signaling pathway. These results may also explain the inhibitory effect of the β4-subunit on cell proliferation.

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions

“…TNIK is a neuronal serine-threonine kinase and scaffold protein that has been implicated in multiple neuronal processes including bidirectional glutamate receptor phosphorylation and the organization of nuclear complexes involved in the regulation of the neuronal transcription factor NeuroD1 [81]. As both β 4 subunit and TNIK are involved in Wnt/β-catenin signaling and transcriptional regulatory mechanisms [81,83,93], interaction of both proteins may regulate the Wnt pathway in neuronal cells and in neurogenesis in particular. In CNS synapses Tnik is concentrated in the postsynaptic density [81].…”

Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay

“…50,51 Interestingly, CACNB4 was shown to translocate to the nucleus to regulate gene expression. 52,53 Different isoforms of the b-subunit of voltage-gated calcium ions channels have been shown to control the transcription of genes by recruiting proteins involved in DNA remodeling such as the heterochromatin protein 1. 54 Also, the b-subunit was reported to downregulate Wnt signaling, a crucial player in neural development, 55 through interaction with the transcription factor TCF4 which is associated with Pitt-Hopkins syndrome (MIM: 610954).…”

“…54 Also, the b-subunit was reported to downregulate Wnt signaling, a crucial player in neural development, 55 through interaction with the transcription factor TCF4 which is associated with Pitt-Hopkins syndrome (MIM: 610954). 53 Mutations in other subunits of voltagegated channels have been associated with mental disorders, autism spectrum disorders (ASD), and cardiovascular problems. [56][57][58][59] In humans, CACNB4 mutations have been associated with episodic ataxia (MIM: 613855) and juvenile myoclonic and idiopathic generalized epilepsy (MIM: 607682).…”

Emerging roles for multifunctional ion channel auxiliary subunits in cancer

“…Ca v βs are functional independent of direct α 1 association. All Ca v βs demonstrate nucleus localisation, Ca v β 4 particularly within nucleoli, and gene expression regulation [ [36] , [37] , [38] , [39] ]. All Ca v βs also contain a Src homology 3 domain capable of regulating endocytosis via interaction with dynamin and can interact with small GTPases [ 40 , 41 ].…”

“…Ca v β 2 is also required for depolarisation-induced c-Fos and meCP2 activation, which intriguingly was shown to be independent of Ca 2+ influx [ 37 ]. Ca v β 4 regulates cell proliferation in vitro [ 44 ], downregulates Wnt signalling via sequestration of the Wnt pathway effector TCF4 [ 39 ], and regulates gene expression via various interacting partners [ 45 , 46 ]. Interestingly, the nuclear localisation of Ca v β 4 was inhibited when co-expressed with Ca v 1.1 and only upon depolarisation and the presence of extracellular Ca 2+ did Ca v β 4 interact with its nuclear signalling partner, B56δ [ 45 ].…”