The concentration of calcium (Ca2+ ions) is normally several thousand times higher outside the cell than inside.
This arrangement is analogous to a homo-tetramer formed by single-domain subunits of voltage-gated potassium channels (that also each contain 6 TM helices).
The 4-domain architecture (and several key regulatory sites, such as the EF hand and IQ domain at the C-terminus) is also shared by the voltage gated sodium channels, which are thought to be evolutionarily related to VGCCs.
[9] VGCCs are subject to rapid inactivation, which is thought to consist of 2 components: voltage-gated (VGI) and calcium-gated (CGI).
The δ subunit has a single transmembrane region with a short intracellular portion, which serves to anchor the protein in the plasma membrane.
Furthermore, the AID sequence does not appear to contain an endoplasmic reticulum retention signal, and this may be located in other regions of the I–II α1 subunit linker.
The γ1 subunit is known to be associated with skeletal muscle VGCC complexes, but the evidence is inconclusive regarding other subtypes of calcium channel.
There are 8 genes for gamma subunits: When a smooth muscle cell is depolarized, it causes opening of the voltage-gated (L-type) calcium channels.
[13][14] Depolarization may be brought about by stretching of the cell, agonist-binding its G protein-coupled receptor (GPCR), or autonomic nervous system stimulation.
(See reference[13] for an illustration of the signaling cascade involving L-type calcium channels in smooth muscle).
L-type calcium channels are also enriched in the t-tubules of striated muscle cells, i.e., skeletal and cardiac myofibers.
[15] As a result, mature neurons express more calcium channels that will only be activated when the cell is significantly depolarized.
[16] Voltage-gated calcium channels antibodies are associated with Lambert-Eaton myasthenic syndrome and have also been implicated in paraneoplastic cerebellar degeneration.
[24][25][26] Also, a CACNA1C risk allele has been associated to a disruption in brain connectivity in patients with bipolar disorder, while not or only to a minor degree, in their unaffected relatives or healthy controls.