Voltage-gated calcium channels: Introduction

INTRODUCTION


The family of voltage-gated calcium channels serve as the key transducers of cell surface membrane potential changes into local intracellular Ca2+ transients that initiate many different physiological events. There are ten members of the voltage-gated Ca2+ 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 Ca2+ channel proteins and provides background information on their molecular, genetic, physiological, and pharmacological properties.

Voltage-gated Ca2+ channels mediate Ca2+ influx in response to membrane depolarization and regulate intracellular processes such as contraction, secretion, neurotransmission, and gene expression in many different cell types [8,62]. 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 [60]. 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 Ca2+ channel family in the Ion Channel Database.

Calcium Channel Subunit Architecture


The Ca2+ channels that have been well-characterized biochemically are complex proteins composed of four or five distinct subunits (Figure 1A; [8,49,51]). 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 α2δ subunit complex, and a transmembrane γ subunit are also components of CaV1.1 Ca2+ channels based on early biochemical studies [51].

The three-dimensional architecture of the skeletal muscle CaV1.1 (Figure 1B) [52,58-59,63] and CaV3.1 [64] channels has been elucidated at 3-4Å by cryo-electron microscopy. Remarkably, the overall organization of subunits within the complex closely resembles the model inferred from the original biochemical studies of the purified CaV1.1 channel complex [51]. 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 α2δ 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 [59]. Increasing evidence indicates that the α2δ subunit is further posttranslationally processed by proteolytic cleavage of its C-terminal transmembrane segment and attachment of a glycosylphosphatidylinositol anchor, which may be crucial for insertion into the plasma membrane at synaptic active zones and for recycling through endosomes for return to the plasma membrane [14].




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 [51]. 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 [59]. 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 Ca2+ 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 Ca2+ selectivity [21]. Although auxiliary subunits modulate the properties of the channel complex, the pharmacological and electrophysiological diversity of Ca2+ channels arise primarily from the existence of multiple α1 subunits [24].

Calcium Channel Selectivity Filter at Atomic Resolution


Based on the amino acid sequences of P-loops of human Ca2+ channels [21], a Ca2+-selective ion selectivity filter was constructed in the bacterial CaV channel construct CaVAb by substitution of three negatively charged amino acid residues on the outer end of the selectivity filter [53]. 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/PNa ~ 0.03) to strongly Ca2+-preferring (PCa/PNa ~ 400) with an overall 12,000-fold difference in selectivity [53]. The additional negative charges create a series of Ca2+ binding sites across the membrane, as observed by x-ray crystallography [53]; Figure 2B, right). Sequential occupancy of these negatively charged coordination sites by Ca2+ yields rapid and selective Ca2+ conductance.




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 [53]. Amino acid residues of T1775 to D181 in stick representation. Green, calcium ions with electron density illustrated in mesh. Red, ordered water molecules.


Ca2+ Currents


Ca2+ currents recorded in different cell types have diverse physiological and pharmacological properties, and an alphabetical nomenclature evolved for the distinct classes of Ca2+ currents [46] [55]). L-type Ca2+ 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 [32,43]. They are the main Ca2+ currents recorded in muscle and endocrine cells, where they initiate contraction and secretion. A subset of L-type Ca2+ currents activating at more negative voltages also are present in neurons and cardiac pacemaker cells. N-type, P/Q-type, and R-type Ca2+ currents also require strong depolarisation for activation [29,32,42]. They are relatively unaffected by L-type Ca2+ antagonist drugs but are blocked by specific polypeptide toxins from snail and spider venoms [33]. They are expressed primarily in neurons, where they initiate neurotransmission at most fast synapses and also mediate Ca2+ entry into cell bodies and dendrites. T-type Ca2+ currents are activated by small depolarisations from resting and are transient [6][38]. They are resistant to both organic antagonists and to the snake and spider toxins used to define the N- and P/Q-type Ca2+ 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.

Ca2+ Channel Classification and Nomenclature


Mammalian α1 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 through α1E for those discovered subsequently [3]. In 2000, a rational nomenclature was adopted [13] based on the well-defined potassium channel nomenclature [10]. Ca2+ 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 channel α1 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 CaV1 subfamily (CaV1.1 to CaV1.4) includes channels containing α1S, α1C, α1D, and α1F subunits, which mediate L-type Ca2+ currents (Table 1). The CaV2 subfamily (CaV2.1 to CaV2.3) includes channels containing α1A, α1B, and α1E, which mediate P/Q-type, N-type, and R-type Ca2+ currents, respectively (Table 1). The CaV3 subfamily (CaV3.1 to CaV3.3) includes channels containing α1G, α1H, 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 Z944, TTA-A2 Pacemaking; repetitive firing
CaV3.2 T Neuronal cell bodies and dendrites; cardiac and smooth muscle myocytes Z944, TTA-A2 Pacemaking; repetitive firing
CaV3.3

T

Neuronal cell bodies and dendrites

Z944, TTA-A2

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 Ca2+ 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).


Ca2+ Channel Interacting Proteins


Ca2+ channels are regulated by transient interactions with G protein βγ subunits, SNARE proteins, calmodulin and related Ca2+ sensor proteins, and phosphorylation by several protein kinases [7,9,24,31] [44,61]. In addition to these transient protein-protein interactions, Ca2+ channel expression and localization are regulated by stable interactions with members of the RGK-family of Ras-like GTP-binding proteins, like Rad and Rem. They bind to the intracellular CaVβ subunit and reduce CaV channel expression [4]. Recent work on Rad indicates that its phosphorylation by the β-adrenergic/protein kinase A signaling pathway contributes importantly to up-regulation of the activity of Cav1.2 channels in the heart in response to stress and exercise [28]. RIM proteins bind to a PDX domain on the C-terminal of CaV2 channels and anchor them at presynaptic active zones [20,26]. They also modulate CaV1 and CaV2 channel activity through their binding to CaVβ-subunits [17,27,36]. The adaptor protein STAC3 binds to Cav1.1 and has been identified as essential component to link Cav1.1 and RyR1 for skeletal muscle EC coupling [16,25,41]. STAC proteins also regulate Ca2+/calmodulin-dependent feedback of L-type Ca2+ channels [5,40]. Binding of α-actinin to the C-terminus of Cav1.2 supports its surface localization and postsynaptic targeting in neurons [19]. It is likely that additional Ca2+ channel interacting proteins will be discovered that regulate channel expression, localization, and function [57].

Ca2+ Channel Molecular Pharmacology


The pharmacology of the three subfamilies of Ca2+ channels is quite distinct. The CaV1 channels are the molecular targets of the organic Ca2+ 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 [18]). 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 CaV1.2 channel protein [24,49]. 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 [23-24,49]. 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 [23-24,49]. 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 CaV1.2 channels with structural studies of the bacterial CaV channel construct CaVAb reveal these two distinct classes of allosteric and pore-blocking binding sites for Ca2+ antagonist drugs are located in close physical proximity on the inner and outer, lipid facing surfaces of the pore domain [54]. 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. Structural studies of the model bacterial channel CavAb revealed a partially overlapping binding position in the pore of the channel for diltiazem and verapamil, indicating that phenylalkylamines and benzothiazepines share overlapping binding sites whose complex drug-binding properties result in allosteric interactions between the bound ligands (Figure 4, left [52]).

Structural studies of the Cav1.1 channel from mammalian skeletal muscle have also revealed the binding sites for the three classes of Ca2+ antagonist drugs that act on Cav1 channels (Figure 4, right [63]). The receptor sites for verapamil and diltiazem closely resemble those found for CavAb. On the other hand, the receptor site for dihydropyridines is slightly, but significantly, different. Amlodipine bound to CavAb lies approximately two helical turns on the extracellular side of nifedipine bound to Cav1.1, at the outer edge of the dihydropyridine receptor site defined by mutagenesis of mammalian Cav1.2 channels [63]. This structural difference likely reflects differences in amino acid sequence in this region of the two Cav channels. Nevertheless, the mechanistic distinction between phenylalkylamines and benzothiazepines as direct pore blockers and dihydropyridines as indirect allosteric inhibitors is retained in these two distantly related Cav channel proteins.



Figure 4. Structure of the drug receptor sites in voltage-gated Ca2+ channels. Left: Top. Top view of the model Ca2+ 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. Right: The position of the pore domain-forming S5 and S6 helices within the rabbit Cav1.1 channel complex (rCav1.1) is shown on the left. The insets show the interaction sites for various Ca2+-channel blockers nifedipine, verapamil and diltiazem as well as the Ca2+-channel activator BAY K 8644 (from Wu et al., 2019, [63]).


The CaV2 subfamily of Ca2+ channels is relatively insensitive to dihydropyridine Ca2+ channel blockers; rather, these Ca2+ channels are specifically blocked with high affinity by peptide toxins from spiders and marine snails [33]. The CaV2.1 channels are blocked specifically by ω-agatoxin IVA from funnel web spider venom. The CaV2.2 channels are blocked specifically by ω-conotoxin GVIA and related cone snail toxins. Amongst the CaV family, CaV2.3 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 CaV2 family of Ca2+ channels.

The CaV3 subfamily of Ca2+ channels is relatively insensitive to both the dihydropyridines that block CaV1 channels and the spider and cone snail toxins that block the CaV2 channels [37]. The organic Ca2+ channel blocker mibefradil is somewhat selective for T-type versus L-type Ca2+ currents (three- to ten-fold). The peptide kurtoxin inhibits the activation gating of CaV3.1 and CaV3.2 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) [12,37]. Z944 has also proven efficacious in humans in an experimental model of neuropathic pain and central sensitization. The cryo-EM structures of human Ca v3.1 alone and in complex with Z944 have been reported recently [64]. For a complete listing of CaV3 inhibitors, please see the individual entries in the Ion Channel Database.

Ca2+ Channelopathies


Mutations in voltage-gated Ca2+ channels cause several forms of inherited disease [31]. Mutations in skeletal muscle CaV1.1 channels cause hypokalemic periodic paralysis [15,31,56]. Mutations that cause loss of voltage-dependent inactivation in cardiac and neuronal CaV1.2 channels cause Timothy Syndrome, a multi-faceted disease that includes cardiac arrhythmia, autism, and developmental abnormalities [30,47-48]. Mutations that cause gain of function in CaV2.1 channels cause migraine headache [39], and mutations that lead to missense substitutions and truncations as well as polyglutamine expansions in the large C-terminal domain of CaV2.1 cause spinocerebellar ataxia type 6 [34,65]. Loss of CaV1.3 function results in sinoatrial node dysfunction and deafness [1], whereas gain of function causes severe neurodevelopmental disorders (including autism) and primary aldosteronism [35]. Loss of function mutations of CaV1.4 channels prevent normal formation of synapses in photoreceptors and cause congenital stationary night blindness type 2 [2,50]. Gain of function mutations in other Cavs also cause disease, including epileptic encephalopathies (Cav2.3) [22], childhood-onset cerebellar ataxia (Cav3.1) [11] and primary aldosteronism (Cav3.2) [45]. More details on these channelopathies are given in the Ion Channel Database entries for each channel type.

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