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Voltage-gated calcium channels are a family of membrane proteins that open in response to membrane depolarisation and allow the passage of calcium ions from the extracellular space into the cytosol of electrically excitable tissues such as nerve, heart and muscle.

Based on their voltage threshold or activation, they are sub-divided into high voltage and low voltage activated channels. High voltage activated channels are heteromultimers comprised of a pore forming Cavα1 subunit, plus ancillary Cavβ, Cavα2δ and in some cases, Cavγ subunits. Low voltage activated channels only contain only a Cavα1 subunit. The Cavα1 subunit contains the major components that are sufficient for forming a voltage sensitive channel whereas the accessory subunits aid the trafficking of the channel to the cell surface, and are capable of modulating biophysical and pharmacological properties of the channel complex.

The mammalian genome encodes four different types of Cavβ subunits, and four Cavα2δ subunit isoforms. The Cavα1 subunit defines the calcium channel subtype: Cav1.1, Cav1.2, Cav1.3 and Cav1.4 all produce L-type currents and are encoded respectively by the CACNA1S, CACNA1C, CACN1ID and CACN1IF genes; Cav2.1 (encoded by CACNA1A), Cav2.2 (CACNA1B) and Cav2.3 (CACNA1E) give rise to, respectively, P/Q-type, N-type and R-type currents. Cav3.1, Cav3.2 and Cav3.3 are all members of the low voltage activated T-type calcium channel family and are represented by the CACNA1G, CACN1IH, and CACNA1I genes.

All ten Cavα1 subunits share a common transmembrane architecture, with four major transmembrane domains (termed domain I through IV) that are flanked by cytoplasmic N- and C-termini and connected by large intracellular linkers. Each transmembrane domain contains six transmembrane helices termed S1 through S6 plus a re-entrant p-loop located between segments S5 and S6 in each domain.

For high voltage activated channels, the Cavα2δ subunit attaches to the extracellular portions of domains I through III, whereas the Cavβ subunits bind to the intracellular linker between domains I and II. Each of the subunits are subject to alternative splicing, thus giving rise to a vast level of calcium channel diversity.

Cryo-electron microscopy structures of representative members of each of the calcium channel families have been resolved and have yielded important insights into the structure, function and pharmacology of the channels.
 

All calcium channels share similar mechanisms of opening, closing and voltage-dependent inactivation. Activation of the channel involves a depolarization induced outward movement of voltage sensing elements comprised of the S4 transmembrane helices in each of the four transmembrane domains.

The S4 helices carry a positively charge amino acid residue in every third position which allows them to respond to voltage changes. The voltage sensor movement lead to a conformational change the opens the pore of the channel thus allowing calcium ions to pass. Membrane hyperpolarization leads to return of the voltage sensors to their resting position, thus closing the channel. During prolonged depolarizations, channels can also enter a voltage dependent inactivation state during which intracellular regions interact with S6 helices to prevent ion permeation.

Cav1 and Cav2 channels also exhibit an additional inactivation mechanism that is dependent on intracellular calcium concentration. Association of the calcium sensing protein calmodulin with the C-terminus regions of the channel acts as a calcium sensor that induces conformational changes and consequently calcium dependent inactivation. Both voltage dependent and calcium dependent inactivation are designed to prevent calcium overload of cells. Channels can recover from voltage dependent inactivation upon membrane hyperpolarization. This allows the channels to be re-opened upon an ensuing membrane depolarization.

Permeation and ion selectivity of the channels are governed by negatively charged amino acid residues in the p-loops of the four transmembrane domains. The combination of these various biophysical properties allows channels to precisely respond to changes in membrane potentials to and permit the entry of calcium ions along their electrochemical gradient in a spatially and temporally controlled manner.

Different types of calcium channels contribute to specific physiological and pathophysiological processes. Cav1.1 channels are expressed in skeletal muscle where their opening is critical for muscle contraction. These particular channels act as voltage-sensors for ryanodine receptors expressed on the sarcoplasmic reticulum, which then release calcium thereby triggering skeletal muscle contraction.

Cav1.2 and Cav1.3 channels are expressed in heart, smooth muscle, endocrine and neuronal tissues. In the heart, calcium entry via Cav1.2 is critical for cardiac muscle contraction. In neuronal tissues, Cav1.2 and Cav1.3 channels are important for synaptic integration and the former also regulate calcium dependent gene transcription. Both channel subtypes are also involved in hormone release. Cav1.3 channels are important for auditory signalling in cochlear hair cells, whereas Cav1.4 channels are expressed in retinal ribbon synapses where they regulate photo transduction.

Cav2.1 and Cav2.2 channels are responsible for mediating calcium-dependent neurotransmitter release in central and peripheral nervous system synapses, with Cav2.1 being critical for the function of neuromuscular junctions. Cav2.3 channels also contribute to neurotransmission, in addition to regulating neuronal excitability.

All members of the Cav3 channel family are thought be important for regulating neuronal firing patterns. They may also play a role in low threshold release of hormones and neurotransmitters, and may have a role in gene transcription.

Many of these physiological features have been examined by the use of selective pharmacological inhibitors of the various calcium channel subtypes, as well as knock-out mouse models that lack the various calcium channel subtypes.

Voltage-gated calcium channels do not exist in isolation, but are often part of larger protein complexes. For example, Cav2.1 and Cav2.2 calcium channels associate with proteins involved in synaptic vesicle exocytosis such as syntaxin 1, SNAP25 and synaptotagmin, and these interactions are critical for fast synaptic transmission.

Several types of calcium channels interact with other types of ion channels such as voltage and calcium dependent potassium channels. For example, Cav3 calcium channels can regulate the function of A-type potassium channels by providing calcium to the calcium-dependent regulatory protein KChIP, and they can activate certain types of calcium dependent potassium channels via calmodulin. Cav2 calcium channels also co-assemble with different types of G-protein coupled receptors which allows efficient control of these receptors over calcium channel activity.

Calcium channels often associate with kinases, phosphatases and small G proteins which can be critical for regulation of calcium channel activity by protein phosphorylation and de-phosphorylation. This is particularly true for Cav1.2 channels whose regulation by protein kinase A and protein kinase A anchoring proteins regulates the flight or fight response in mammals. Several types of calcium channels have been shown to interact with ubiquitin ligases and de-ubiquitinases which are enzymes that regulate protein stability and degradation of the channels.

There are numerous other examples of calcium channels associating with regulatory proteins. It is important to note that pathological variants in calcium channel genes that create severe pathology do not always result in large alterations in the biophysical properties of the channels.

One potential explanation may be that mutations in calcium channels genes may disrupt interactions with regulatory proteins, or with calcium dependent proteins such as calmodulin, which then secondarily affects downstream cell signaling processes without altering calcium entry though the channels per se.
 

While we have learned much about the structure, function, physiology and pharmacology of calcium channels, much remains to be elucidated.

Among the various calcium channel subtypes, the Cav3.3 is the least best understood in terms of precise physiological function. Alternative splicing of various calcium channel subunits can give rise to a great amount of functional diversity, but which precise exon combinations are preferentially expressed for a given calcium channel subtype across different tissues, different brain regions, and different stages of development has not been fully explored.

Given that some pathological variants in Cav2.1 and Cav3.2 calcium channels manifest themselves differentially in channels comprised of different exon combinations, such knowledge is critical towards understanding how a variant contributes to pathology.

Finally, a single variant in a calcium channel may manifest itself differently in two individuals, because of interactions with other genetic or epigenetic mechanisms and this remains to be explored further.