Channelpedia

Cavβ4

Description: calcium channel, voltage-dependent, beta 4 subunit
Gene: cacnb4
Alias: cacnb4, CAB4, CACNLB4, EA5, EIG9, EJM, EJM4, EJM6

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Introduction

CACNB4 (also known as EA5; EJM; CAB4; EIG9; EJM4; EJM6; CACNLB) encodes a member of the beta subunit family of voltage-dependent calcium channel complex proteins. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. The protein encoded by this locus plays an important role in calcium channel function by modulating G protein inhibition, increasing peak calcium current, controlling the alpha-1 subunit membrane targeting and shifting the voltage dependence of activation and inactivation. Certain mutations in this gene have been associated with idiopathic generalized epilepsy (IGE) and juvenile myoclonic epilepsy (JME). Multiple transcript variants encoding different isoforms have been found for this gene.

http://www.ncbi.nlm.nih.gov/gene/785

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Gene

Alternative splicing of different full-length b subunit isoforms not only generates variable coding sequences for N-terminal, HOOK, and C-terminal domains but also generates shorter variants with truncated Src homology 3 and/or GK domains. These variants result from splicing-induced frameshifts and subsequent early stop codons (Foell [1308], Hibino [1309]).

Species NCBI gene ID Chromosome Position
Human 785 2 266396
Mouse 12298 2 248484
Rat 58942 3 262420
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Transcript

Species NCBI accession Length (nt)
Human NM_001005747.4 8074
Mouse NM_001037099.2 8008
Rat NM_001399143.1 8101
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Protein Isoforms

Species Uniprot ID Length (aa)
Human O00305 520
Mouse Q8R0S4 519
Rat D4A055 519

Isoforms

Transcript
Length (nt)
Protein
Length (aa)
Variant
Isoform
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Post-Translational Modifications

PTM
Position
Type
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Structure

Voltage-gated Ca2+ channels are multisubunit proteins composed of a pore-forming alpha1 subunit, a two-part alpha2delta/gamma integral membrane subunit, and a soluble cytosolic beta subunit (Dolphin [251]). The auxiliary beta subunit functions both as a chaperone in trafficking the channel complex to the plasma membrane and as a major regulator of channel gating (opening and closing). These functions are thought to occur mainly through a specific interaction between the beta subunit and the alpha1 interaction domain of the intracellular loop between alpha1 repeat motifs I and II (de Waard [1301]).

Sequence comparisons led to the initial discovery that Ca2+ channel b subunits are membrane- associated guanylate kinase proteins consisting of core Src homology 3 and guanylate kinase (GK)2 domains connected by a large variable loop (HOOK) (Hanlon [1304]). The core is flanked by highly variable N- and C-terminal domains. High resolution x-ray crystallographic studies further confirmed the structure of the b subunit core domains and determined that the interaction between the b and alpha1 subunits occurs via GK domain binding with high affinity to the alpha1 interaction domain of alpha1 (Chen [1254], Opatowsky [1305], Petegem [1306], Petegem 2008 [1307]).

Cavβ4 predicted AlphaFold size

Species Area (Å2) Reference
Human 4783.84 source
Mouse 4785.07 source
Rat 4576.56 source

Methodology for AlphaFold size prediction and disclaimer are available here

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Expression and Distribution

An alternatively spliced, truncated b4 subunit (b4c) was identified in the human brain and shown to be highly expressed in nuclei of vestibular and deep cerebellar neurons. (Xu [1293])

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Function

Zebrafish embryos lacking b4 subunits failed to initiate epiboly and the underlying mechanism for this phenomenon maybe related to the high levels of b4 expression in yolk syncytial nuclei (Ebert [1302]). Other studies have shown that b subunit functions in the nucleus may be cell type- and splice variant-specific (Subramanyam [1303]).

b4c subunit belongs to the PXVXL protein family with epigenetic responsibilities. These proteins have multiple nuclear functions, including transcription regulation (TIF1a) and nucleosome assembly (CAF1). (Xu [1293])

References

251

Dolphin AC Calcium channel diversity: multiple roles of calcium channel subunits.
Curr. Opin. Neurobiol., 2009 Jun , 19 (237-44).

1254

Chen YH et al. Structural basis of the alpha1-beta subunit interaction of voltage-gated Ca2+ channels.
Nature, 2004 Jun 10 , 429 (675-80).

1295

Graves TD et al. Episodic ataxia: SLC1A3 and CACNB4 do not explain the apparent genetic heterogeneity.
J. Neurol., 2008 Jul , 255 (1097-9).

1296

von Brevern M et al. Migrainous vertigo: mutation analysis of the candidate genes CACNA1A, ATP1A2, SCN1A, and CACNB4.
Headache, 2006 Jul-Aug , 46 (1136-41).

1300

Day NC et al. The expression of voltage-dependent calcium channel beta subunits in human hippocampus.
Brain Res. Mol. Brain Res., 1998 Oct 1 , 60 (259-69).

1301

De Waard M et al. Ca2+ channel regulation by a conserved beta subunit domain.
Neuron, 1994 Aug , 13 (495-503).

1302

Ebert AM et al. Ca2+ channel-independent requirement for MAGUK family CACNB4 genes in initiation of zebrafish epiboly.
Proc. Natl. Acad. Sci. U.S.A., 2008 Jan 8 , 105 (198-203).

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Credits

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/91/ , accessed on 2024 Dec 21


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