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Group of voltage gated ion channels permeable to Ca2+

Voltage gated calcium channels (VGCCs), also known as voltage dependent calcium channels (VDCCs), are a group of voltage gated ion channels found in the membrane of excitable cells (e. g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+–Na+ channels, but their permeability to calcium is about 1000 fold greater than to sodium under normal physiological conditions. At physiologic or resting membrane potential, VGCCs are normally closed. They are activated (i. e.: opened) at depolarized membrane potentials and this is the source of the "voltage gated" epithet. The concentration of calcium (Ca2+ ions) is normally several thousand times higher outside the cell than inside. Activation of particular VGCCs allows a Ca2+ influx into the cell, which, depending on the cell type, results in activation of calcium sensitive potassium channels, muscular contraction, excitation of neurons, up regulation of gene expression, or release of hormones or neurotransmitters. VGCCs have been immunolocalized in the zona glomerulosa of normal and hyperplastic human adrenal, as well as in aldosterone producing adenomas (APA), and in the latter T type VGCCs correlated with plasma aldosterone levels of patients. Excessive activation of VGCCs is a major component of excitotoxicity, as severely elevated levels of intracellular calcium activates enzymes which, at high enough levels, can degrade essential cellular structures.

Voltage gated calcium channels are formed as a complex of several different subunits: α1, α2δ, β1 4, and γ. The α1 subunit forms the ion conducting pore while the associated subunits have several functions including modulation of gating.

When a smooth muscle cell is depolarized, it causes opening of the voltage gated (L type) calcium channels. Depolarization may be brought about by stretching of the cell, agonist binding its G protein coupled receptor (GPCR), or autonomic nervous system stimulation. Opening of the L type calcium channel causes influx of extracellular Ca2+, which then binds calmodulin. The activated calmodulin molecule activates myosin light chain kinase (MLCK), which phosphorylates the myosin in thick filaments. Phosphorylated myosin is able to form crossbridges with actin thin filaments, and the smooth muscle fiber (i. e., cell) contracts via the sliding filament mechanism. (See reference As a result, mature neurons express more calcium channels that will only be activated when the cell is significantly depolarized. The different expression levels of low voltage activated (LVA) and high voltage activated (HVA) channels can also play an important role in neuronal differentiation. In developing Xenopus spinal neurons LVA calcium channels carry a spontaneous calcium transient that may be necessary for the neuron to adopt a GABAergic phenotype as well as process outgrowth.

Voltage gated calcium channels antibodies are associated with Lambert Eaton myasthenic syndrome and have also been implicated in paraneoplastic cerebellar degeneration. Voltage gated calcium channels are also associated with malignant hyperthermia and Timothy syndrome. Mutations of the CACNA1C gene, with a single nucleotide polymorphism in the third intron of the Cav1.2 gene, are associated with a variant of long QT syndrome called Timothy's syndrome and also with Brugada syndrome. Large scale genetic analyses have shown the possibility that CACNA1C is associated with bipolar disorder and subsequently also with schizophrenia. 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.