The family of voltage-gated calcium channels serve as the key transducers of cell surface membrane potential changes into local intracellular calcium transients that initiate many different physiological events. There are ten members of the voltage-gated calcium channel family that have been characterized in mammals, and they serve distinct roles in cellular signal transduction. This article introduces the molecular relationships and physiological functions of these calcium channel proteins and provides background information on their molecular, genetic, physiological, and pharmacological properties.
Voltage-gated calcium channels mediate calcium influx in response to membrane depolarization and regulate intracellular processes such as contraction, secretion, neurotransmission, and gene expression in many different cell types (Catterall, 2011). Their activity is essential to couple electrical signals in the cell surface to physiological events in cells. They are members of a gene superfamily of transmembrane ion channel proteins that includes voltage-gated potassium and sodium channels (Yu and Catterall, 2004). This article presents an introduction to their biochemical, molecular, and genetic properties, their physiological roles, and their pharmacological significance, as an introduction to the comprehensive information on each member of the calcium channel family in the Ion Channel Database.
Calcium Channel Subunit Architecture
The calcium channels that have been well-characterized biochemically are complex proteins composed of four or five distinct subunits (Figure 1A; (Catterall, 2011; Striessnig, 1999; Takahashi et al., 1987)). The α1
subunit of 190–250 kDα is the largest subunit and it incorporates the conduction pore, the voltage sensor and gating apparatus, and most of the known sites of channel regulation by second messengers, drugs, and toxins. An intracellular β subunit, a transmembrane, disulfide-linked α2
δ subunit complex, and a transmembrane γ subunit are also components of CaV
1.1 calcium channels based on early biochemical studies (Takahashi et al., 1987).
The three-dimensional architecture of the skeletal muscle CaV
1.1 channels has been elucidated at 4Å by cryo-electron microscopy (Figure 1B; (Wu et al., 2015, 2016)). Remarkably, the overall organization of subunits within the complex closely resembles the model inferred from the original biochemical studies of the purified CaV
1.1 channel complex (Takahashi et al., 1987). The pore-forming α1
subunit is the central transmembrane component, with 24 transmembrane segments surrounding a central pore. The β subunit is located on the cytoplasmic side of the complex interacting primarily with the intracellular surfaces of domains I and II of the α1
subunit. The γ subunit is in a transmembrane position, with its four transmembrane segments interacting primarily with domain IV of the α1
subunit. The proteolytically processed, disulfide-linked α2
δ subunit is in an extracellular position, interacting primarily with the extracellular surface of domains I-III of the α1
subunit. It is associated with the membrane through the δ subunit, but the transmembrane attachment is not shown clearly in the available cryo-EM structures (Wu et al., 2015).
Figure 1. Subunit architecture of calcium channels. Left. The subunit architecture of the skeletal muscle CaV1.1 channel is depicted as described in original biochemical studies (Takahashi et al., 1987). P, protein phosphorylation. Curvy lines, glycosylation. Right. The subunit architecture of the skeletal muscle CaV1.1 channel is depicted as revealed in cryo-electron microscopy studies (Wu et al., 2015). The different subdomains of the α2δ-1 subunit are shown in different colors: Von Willebrand Factor domain (green), Cache domain 1 (brown), and Cache domain 2 (purple). CTD, C-terminal domain.
Like the α subunits of sodium channels, the α1
subunit of voltage-gated calcium channels is organised in four homologous domains (I–IV) with six transmembrane segments (S1–S6) in each (Figure 2A). The S4 segment contains the gating charges, which sense changes in the electric field and initiate conformational changes that open the pore. The pore loop between transmembrane segments S5 and S6 in each domain determines ion conductance and selectivity. Changes of only three amino acids in the pore loops in domains I, III, and IV will convert a sodium channel to calcium selectivity (Heinemann et al., 1992). Although auxiliary subunits modulate the properties of the channel complex, the pharmacological and electrophysiological diversity of calcium channels arise primarily from the existence of multiple α1
subunits (Hofmann et al., 1994).
Calcium Channel Selectivity Filter at Atomic Resolution
Based on the amino acid sequences of P-loops of human calcium channels (Heinemann et al., 1992), a Ca2+
-selective ion selectivity filter was constructed in the bacterial CaV
channel construct CaV
Ab by substitution of three negatively charged amino acid residues on the outer end of the selectivity filter (Tang et al., 2014). This small molecular change does not change the conformation of the selectivity filter at all (Figure 2B, left), but it is sufficient to change the ion selectivity from strongly Na+-preferring (PCa
~ 0.03) to strongly Ca2+
~ 400) with an overall 12,000-fold difference in selectivity (Tang et al., 2014). The additional negative charges create a series of Ca2+
binding sites across the membrane, as observed by x-ray crystallography ((Tang et al., 2014); Figure 2B, right). Sequential occupancy of these negatively charged coordination sites by Ca2+
yields rapid and selective Ca2+
Figure 2. Structure of calcium channels. A. A transmembrane folding diagram of the voltage-gated calcium channel α11.1 subunit. Transmembrane segments S1-S4 form the voltage-sensing module. The S4 segments with their positive gating charges are highlighted in yellow. Transmembrane segments S5 and S6 and the P loop between them are highlighted in green. B. Structural basis for selective calcium conductance. Left. Superimposed high-resolution images of the ion selectivity filters of the bacterial sodium channel NaVAb and its Ca2+-selective derivative CaVAb. Native amino acid residues of NaVAb are in black; substituted amino acid residues in CaVAb are in red. Right. High-resolution structure of the calcium selectivity filter in CaVAb (Tang et al., 2014). Amino acid residues of T1775 to D181 in stick representation. Green, calcium ions with electron density illustrated in mesh. Red, ordered water molecules.
Calcium currents recorded in different cell types have diverse physiological and pharmacological properties, and an alphabetical nomenclature evolved for the distinct classes of calcium currents (Snutch et al., 1990; Tsien et al., 1995). L-type calcium currents typically require a strong depolarisation for activation, are long-lasting, and are blocked by the organic L-type calcium antagonists, including dihydropyridines, phenylalkylamines, and benzothiazepines (Nowycky et al., 1985; Reuter, 1979). They are the main calcium currents recorded in muscle and endocrine cells, where they initiate contraction and secretion. A subset of L-type calcium currents activating at more negative voltages also are present in neurons and cardiac pacemaker cells. N-type, P/Q-type, and R-type calcium currents also require strong depolarisation for activation (Llinas et al., 1992; Nowycky et al., 1985; Randall and Tsien, 1995). They are relatively unaffected by L-type calcium antagonist drugs but are blocked by specific polypeptide toxins from snail and spider venoms (Olivera et al., 1994). They are expressed primarily in neurons, where they initiate neurotransmission at most fast synapses and also mediate calcium entry into cell bodies and dendrites. T-type calcium currents are activated by small depolarisations from resting and are transient (Carbone and Lux, 1984; Perez-Reyes, 2003; Perez-Reyes et al., 1998). They are resistant to both organic antagonists and to the snake and spider toxins used to define the N- and P/Q-type calcium currents. T-type channels are expressed in a wide variety of cell types, where they are involved in shaping the action potential and controlling patterns of repetitive firing.
Calcium Channel Classification and Nomenclature
subunits are encoded by ten distinct genes. Historically, various names had been given to the corresponding gene products, giving rise to distinct and sometimes confusing nomenclatures. In 1994, a unified, but arbitrary nomenclature was adopted in which α1
subunits were referred to as α1S
for the original skeletal muscle isoform and α1A
for those discovered subsequently (Birnbaumer et al., 1994). In 2000, a rational nomenclature was adopted (Ertel et al., 2000) based on the well-defined potassium channel nomenclature (Chandy and Gutman, 1993). Calcium channels were named using the chemical symbol of the principal permeating ion (Ca) with the principal physiological regulator (voltage) indicated as a subscript (CaV
). The numerical identifier corresponds to the CaV
subunit gene subfamily (1 to 3) and the order of discovery of the α1
subunit within that subfamily (1 through n). According to this nomenclature, the CaV
1 subfamily (CaV
1.1 to CaV
1.4) includes channels containing α1S
, and α1F
subunits, which mediate L-type Ca2+
currents (Table 1). The CaV
2 subfamily (CaV
2.1 to CaV
2.3) includes channels containing α1A
, and α1E
, which mediate P/Q-type, N-type, and R-type Ca2+
currents, respectively (Table 1). The CaV
3 subfamily (CaV
3.1 to CaV
3.3) includes channels containing α1G
, and α1I
, which mediate T-type Ca2+
currents (Table 1).TABLE 1. Physiological function and pharmacology of calcium channels.
| Channel || Current || Localization || Specific Antagonists* || Cellular Functions |
| CaV1.1 || L || Skeletal muscle; transverse tubules || Dihydropyridines; phenylalkylamines; benzothiazepines || Excitation-contraction coupling; excitation-transcription coupling |
| CaV1.2 || L || Cardiac myocytes; smooth muscle myocytes; endocrine cells; neuronal cell bodies; proximal dendrites || Dihydropyridines; phenylalkylamines; benzothiazepines || Excitation-contraction coupling; hormone release; regulation of transcription; synaptic integration |
| CaV1.3 || L || Endocrine cells; neuronal cell bodies and dendrites; cardiac atrial myocytes and pacemaker cells; cochlear hair cells || Dihydropyridines; phenylalkylamines; benzothiazepines || Hormone release; regulation of transcription; synaptic regulation; cardiac pacemaking; hearing; neurotransmitter release from sensory cells |
| CaV1.4 || L || Retinal rod and bipolar cells || Dihydropyridines (low affinity) || Neurotransmitter release from photoreceptors |
| CaV2.1 || P/Q || Nerve terminals and dendrites; neuroendocrine cells || ω-Agatoxin IVA || Neurotransmitter release; dendritic Ca2+ transients; hormone release |
| CaV2.2 || N || Nerve terminals and dendrites; neuroendocrine cells || ω-Conotoxin-GVIA || Neurotransmitter release; dendritic Ca2+ transients; hormone release |
| CaV2.3 || R || Neuronal cell bodies and dendrites || SNX-482 || Repetitive firing; dendritic Ca2+ transients |
| CaV3.1 || T || Neuronal cell bodies and dendrites; cardiac and smooth muscle myocytes || None || Pacemaking; repetitive firing |
| CaV3.2 || T || Neuronal cell bodies and dendrites; cardiac and smooth muscle myocytes || None || Pacemaking; repetitive firing |
| CaV3.3 |
| T || Neuronal cell bodies and dendrites || None || Pacemaking; repetitive firing |
* Here we list only the primary localisations and the standard antagonists most widely used in research. Much more detail is given in the Ion Channel Database.
The complete amino acid sequences of these α1 subunits are more than 70% identical within a subfamily but less than 40% identical among the three subfamilies. These family relationships are illustrated for the conserved transmembrane and pore domains in Figure 3. Division of calcium channels into these three families is phylogenetically ancient, as one representative of each is found in the C. elegans genome. Consequently, the genes for the different α1 subunits have become widely dispersed in the genome and even the most closely related members of the family are not clustered on single chromosomes in mammals.
Figure 3. Sequence similarity of voltage-gated calcium channel α1 subunits. Comparison of the amino acid sequence similarity of mammalian calcium channels. Only the membrane-spanning regions and pore loops are compared. All sequence pairs were aligned and compared, which led to the clear separation of the three subfamilies (CaV1, CaV2, CaV3) that have internal sequence identity of >80%. Consensus sequences were defined for all three families and compared to one another, yielding inter-family sequence identity of 52% (CaV1 vs. CaV2) and 28% (CaV3 vs. CaV1 or CaV2).
Calcium Channel Interacting Proteins
Calcium channels are regulated by transient interactions with G protein βγ subunits, SNARE proteins, calmodulin and related calcium sensor proteins, and phosphorylation by several protein kinases (Catterall, 2000, 2015; Catterall and Few, 2008; Hofmann et al., 1999; Reuter, 1983; Zamponi et al., 2015). In addition to these transient protein-protein interactions, calcium channel expression and localization are regulated by stable interactions with Rem proteins and RIM proteins. Rem proteins, which are small GTPases of the RGK family, bind to the intracellular CaV
β subunit and reduce CaV
channel expression (Buraei and Yang, 2015). RIM proteins bind to a PDX domain on the C-terminal of CaV
2 channels and anchor them at presynaptic active zones (Han et al., 2011; Kaeser et al., 2011) They also modulate CaV
1 and CaV
2 channel activity through their binding to CaV
β-subunits (Gebhart et al., 2010; Kiyonaka et al., 2007). It is likely that additional calcium channel interacting proteins will be discovered that regulate channel expression, localization, and function.
Calcium Channel Molecular Pharmacology
The pharmacology of the three subfamilies of calcium channels is quite distinct. The CaV
1 channels are the molecular targets of the organic calcium channel blockers used widely in the therapy of cardiovascular diseases. These drugs are thought to act at three separate, but allosterically coupled, receptor sites (Table 1; reviewed in (Glossmann and Striessnig, 1990)). A combination of photoaffinity labeling, site-directed mutagenesis, and molecular modeling provided an initial view of the location of the drug receptor sites for dihydropyridines, phenylalkylamines, and diltiazem on the CaV
1.2 channel protein (Hockerman et al., 1997; Hofmann et al., 1999; Striessnig, 1999). Phenylalkylamines are intracellular pore blockers, which are thought to enter the pore from the cytoplasmic side of the channel and block it. Their receptor site is formed by amino acid residues in the S6 segments in domains III and IV, in close analogy to the local anaesthetic receptor site on sodium channels (Hockerman et al., 1997; Hofmann et al., 1999; Striessnig, 1999). Dihydropyridines can be channel activators or inhibitors, and therefore are thought to act allosterically to shift the channel toward the open or closed state, rather than by occluding the pore. Their receptor site includes amino acid residues in the S6 segments of domains III and IV and the S5 segment of domain III. The dihydropyridine receptor site is closely apposed to the phenylalkylamine receptor site and shares some common amino acid residues (Hockerman et al., 1997; Hofmann et al., 1999; Striessnig, 1999). Diltiazem and related benzothiazepines are thought to bind to a third receptor site, although the amino acid residues required for their binding overlap extensively with those required for phenylalkylamine binding. Comparison of structure-function studies of mammalian CaV
1.2 channels with structural studies of the bacterial CaV
channel construct CaV
Ab reveal these two distinct classes of allosteric and pore-blocking binding sites for calcium antagonist drugs are located in close physical proximity on the inner and outer, lipid facing surfaces of the pore domain (Tang et al., 2016). As viewed from the top, the four voltage sensor modules are seen in symmetric positions in the periphery of the structure in blue, whereas the pore module is seen in the center of the structure in gray (Figure 4). Amlodipine is shown in its binding site on the outer, lipid-facing wall of the pore domain (Figure 4, top). In contrast, the phenylalkylamine verapamil binds in the pore at the base of the ion selectivity filter, as illustrated in side view of a cross section through the structure (Figure 4, bottom). The locations of these drug binding sites in the three-dimensional structure reveal how phenylalkylamines act as direct, physical pore blockers while the dihydropyridines are allosteric modulators of channel function.
Figure 4. Structure of the drug receptor sites in a model voltage-gated calcium channel. Top. Top view of the model calcium channel CaVAb. Voltage-sensing domains in blue; pore domain in gray. Ca2+ is bound in the central pore (red), and amlodipine is bound to its receptor site on the outer surface of the pore domain. Bottom. Side view. A cross section of CaVAb with verapamil bound in the central CaVity in the pore, just below the ion selectivity filter.
2 subfamily of calcium channels is relatively insensitive to dihydropyridine calcium channel blockers; rather, these calcium channels are specifically blocked with high affinity by peptide toxins from spiders and marine snails (Olivera et al., 1994). The CaV
2.1 channels are blocked specifically by ω-agatoxin IVA from funnel web spider venom. The CaV
2.2 channels are blocked specifically by ω-conotoxin GVIA and related cone snail toxins. Amongst the CaV
2.3 channels are blocked specifically by the synthetic peptide toxin SNX-482 derived from tarantula venom. These peptide toxins are potent blockers of synaptic transmission because of their specific effects on the CaV
2 family of calcium channels.
3 subfamily of calcium channels is relatively insensitive to both the dihydropyridines that block CaV
1 channels and the spider and cone snail toxins that block the CaV
2 channels (Perez-Reyes, 2003). The organic calcium channel blocker mibefradil is somewhat selective for T-type versus L-type calcium currents (three- to ten-fold). The peptide kurtoxin inhibits the activation gating of CaV
3.1 and CaV
3.2 channels. Recently a number of pharmacological agents have been developed that selectively block T-type calcium currents, and these have been shown to be useful in models of neuropathic pain, epilepsy and psychiatric comorbidities (e.g., TTA-A2, TTA-P2, and Z944 ; (Perez-Reyes, 2003; Choe et al., 2011). Z944 has also proven efficacious in humans in an experimental model of neuropathic pain and central sensitization. For a complete listing of CaV
3 inhibitors, please see the individual entries in the Ion Channel Database.
Mutations in voltage-gated calcium channels cause several forms of inherited disease. Mutations in skeletal muscle CaV
1.1 channels cause hypokalemic periodic paralysis (Venance et al., 2006). Mutations that cause loss of voltage-dependent inactivation in cardiac and neuronal CaV
1.2 channels cause Timothy Syndrome, a multi-faceted disease that includes cardiac arrhythmia, autism, and developmental abnormalities (Splawski et al., 2005; Splawski et al., 2004). Mutations that cause gain of function in CaV
2.1 channels cause migraine headache (Pietrobon and Striessnig, 2003), and mutations that lead to missense substitutions and truncations as well as polyglutamine expansions in the large C-terminal domain of CaV
2.1 cause spinocerebellar ataxia (Ophoff et al., 1996; Zhuchenko et al., 1997). Loss of CaV
1.3 function results in sinoatrial node dysfunction and deafness (Baig et al., 2011). Mutations that block expression of CaV
1.4 channels prevent normal formation of synapses in photoreceptors and cause congenital stationary night blindness (Bech-Hansen et al., 1998; Strom et al., 1998). More details on these channelopathies are given in the Ion Channel Database entries for each channel type.
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