Cavβ4
Description: calcium channel, voltage-dependent, beta 4 subunit Gene: cacnb4 Alias: cacnb4, CAB4, CACNLB4, EA5, EIG9, EJM, EJM4, EJM6
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
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]).
Transcript
| Species | NCBI accession | Length (nt) | |
|---|---|---|---|
| Human | NM_001005747.4 | 8074 | |
| Mouse | NM_001037099.2 | 8008 | |
| Rat | NM_001399143.1 | 8101 |
Protein Isoforms
Isoforms
Post-Translational Modifications
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
Methodology for AlphaFold size prediction and disclaimer are available here
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])
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
Dolphin AC
Calcium channel diversity: multiple roles of calcium channel subunits.
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2009
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, 19 (237-44).
Chen YH
et al.
Structural basis of the alpha1-beta subunit interaction of voltage-gated Ca2+ channels.
Nature,
2004
Jun
10
, 429 (675-80).
Xu X
et al.
The Ca2+ channel beta4c subunit interacts with heterochromatin protein 1 via a PXVXL binding motif.
J. Biol. Chem.,
2011
Mar
18
, 286 (9677-87).
Ohmori I
et al.
A CACNB4 mutation shows that altered Ca(v)2.1 function may be a genetic modifier of severe myoclonic epilepsy in infancy.
Neurobiol. Dis.,
2008
Dec
, 32 (349-54).
Graves TD
et al.
Episodic ataxia: SLC1A3 and CACNB4 do not explain the apparent genetic heterogeneity.
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2008
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, 255 (1097-9).
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).
Vendel AC
et al.
Alternative splicing of the voltage-gated Ca2+ channel beta4 subunit creates a uniquely folded N-terminal protein binding domain with cell-specific expression in the cerebellar cortex.
J. Neurosci.,
2006
Mar
8
, 26 (2635-44).
Vendel AC
et al.
Solution structure of the N-terminal A domain of the human voltage-gated Ca2+channel beta4a subunit.
Protein Sci.,
2006
Feb
, 15 (378-83).
Helton TD
et al.
Alternative splicing of the beta 4 subunit has alpha1 subunit subtype-specific effects on Ca2+ channel gating.
J. Neurosci.,
2002
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1
, 22 (1573-82).
Day NC
et al.
The expression of voltage-dependent calcium channel beta subunits in human hippocampus.
Brain Res. Mol. Brain Res.,
1998
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1
, 60 (259-69).
De Waard M
et al.
Ca2+ channel regulation by a conserved beta subunit domain.
Neuron,
1994
Aug
, 13 (495-503).
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).
Subramanyam P
et al.
Activity and calcium regulate nuclear targeting of the calcium channel beta4b subunit in nerve and muscle cells.
Channels (Austin),
2009 Sep-Oct
, 3 (343-55).
Hanlon MR
et al.
Modelling of a voltage-dependent Ca2+ channel beta subunit as a basis for understanding its functional properties.
FEBS Lett.,
1999
Feb
26
, 445 (366-70).
Opatowsky Y
et al.
Structural analysis of the voltage-dependent calcium channel beta subunit functional core and its complex with the alpha 1 interaction domain.
Neuron,
2004
May
13
, 42 (387-99).
Van Petegem F
et al.
Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain.
Nature,
2004
Jun
10
, 429 (671-5).
Van Petegem F
et al.
Alanine-scanning mutagenesis defines a conserved energetic hotspot in the CaValpha1 AID-CaVbeta interaction site that is critical for channel modulation.
Structure,
2008
Feb
, 16 (280-94).
Foell JD
et al.
Molecular heterogeneity of calcium channel beta-subunits in canine and human heart: evidence for differential subcellular localization.
Physiol. Genomics,
2004
Apr
13
, 17 (183-200).
Hibino H
et al.
Direct interaction with a nuclear protein and regulation of gene silencing by a variant of the Ca2+-channel beta 4 subunit.
Proc. Natl. Acad. Sci. U.S.A.,
2003
Jan
7
, 100 (307-12).
Credits
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