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.
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 , Hibino ).
A protein complex that forms a transmembrane channel through which calcium ions may pass in response to changes in membrane potential.
The junction between a nerve fiber of one neuron and another neuron or muscle fiber or glial cell; the site of interneuronal communication. As the nerve fiber approaches the synapse it enlarges into a specialized structure, the presynaptic nerve ending, which contains mitochondria and synaptic vesicles. At the tip of the nerve ending is the presynaptic membrane; facing it, and separated from it by a minute cleft (the synaptic cleft) is a specialized area of membrane on the receiving cell, known as the postsynaptic membrane. In response to the arrival of nerve impulses, the presynaptic nerve ending secretes molecules of neurotransmitters into the synaptic cleft. These diffuse across the cleft and transmit the signal to the postsynaptic membrane.
The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins.
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 ). 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 ).
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 ). 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 , Opatowsky , Petegem , Petegem 2008 ).
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 )
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 ). Other studies have shown that b subunit functions in the nucleus may be cell type- and splice variant-specific (Subramanyam ).
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 )