Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Voltage-Gated Calcium Channels: Structure and Function (CACNA)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_145

Synonyms

Historical Background

Voltage-gated calcium channels (CaV) are a family of complex proteins that conduct Ca2+ into the cell cytoplasm through a large pore-forming α1 subunit of 190–250 kDa. They are divided into three major families CaV1.x, CaV2.x, and CaV3.x based on sequence homology of the α1 subunit. In turn, each subfamily is comprised of four (CaV1.1–CaV1.4) or three (CaV2.1–2.3; CaV3.1–3.3) members derived from separate genes (Catterall et al. 2005). The α1 subunits are variably associated with β, α2δ, and γ accessory proteins that modulate expression, targeting, voltage dependence, and kinetic characteristics (Fig. 1a) (Catterall et al. 2005; Buraei and Yang 2010). Moreover, splice variants of the α1 subunit can account for tissue-specific behavior. Alternate classification schemes exist. Table 1 shows the early nomenclature; L-, P/Q-, N-, R-, and T-type, and its relationship to more modern schemes based on sequence identification. The order of molecular identification of the α1 subunit defines the skeletal muscle α1 subunit as α1S, and subsequent genes as α1A–α1I (i.e., a total of ten genes: α1S, α1A–α1I). Amino acid homology can exceed ∼80% within families but may be less than 30% between families (Fig. 2). In all cases, α1 subunit structure includes four homologous domains (I–IV) each of which is comprised of six (S1–S6) membrane-spanning regions (Fig. 1b). Voltage sensing resides in the S4 regions of the domains, and the reentrant “P-loop” between S5 and S6 provides the selectivity filter. Other important regions include the inactivation gate and, in some channels, a site for calmodulin binding. The site of CaM binding to the IQ domain of the C-terminus has been proposed to confer local (near the channel pore) versus global (cytoplasmic) sensing of calcium (Liang et al. 2003). Both N-terminal and C-termini are intracellular. CaV bear structural resemblance to voltage-gated potassium and sodium channels, implying a common ancestry. Indeed, minor modifications within the pore-forming sequences of CaV can yield Na+ selectivity and CaV commonly conduct Na+ ions in Ca2+-free extracellular solutions. These channels are of ancient origin; examples of each subfamily are found in Caenorhabditis elegans.
Voltage-Gated Calcium Channels: Structure and Function (CACNA), Fig. 1

Voltage-gated calcium channel (CaV) structure. (a) CaV are comprised of the α1 pore-forming subunit and accessory α2δ, β, and γ accessory proteins. (b) Topology of CaV α1 subunit. The α1 subunit is comprised of four domains (I–IV) each of which contains six membrane-spanning regions (S1–S6) and an intramembranous “P” loop that forms the selectivity filter. Voltage sensing is attributed to membrane-potential-dependent displacement of positively charged residues in the S4 region. The α interaction domain (AID, red) on intracellular loop I-II binds the β subunit (Adapted with permission from Buraei and Yang 2010)

Voltage-Gated Calcium Channels: Structure and Function (CACNA), Table 1

Voltage-gated Ca2+ channel (CaV) classification. Listing and comparison of voltage-gated calcium channel (CaV) classifications in common use

  

CaV

α1 subunit

Gene symbol

Human chromosome

HVA

L

1.1

1S

CACNA1S

1q32

L

1.2

1C

CACNA1C

12p13.3

L

1.3

1D

CACNA1D

3p14.3

L

1.4

1F

CACNA1F

Xp11.23

HVA

P/Q

2.1

1A

CACNA1A

19p13

N

2.2

1B

CACNA1B

9q34

R

2.3

1E

CACNA1E

1q25-q31

LVA

T

3.1

1G

CACNA1G

17q22

T

3.2

1H

CACNA1H

16p13.3

T

3.3

1I

CACNA1I

22q13.1

HVA high voltage activated, LVA low voltage activated

Voltage-Gated Calcium Channels: Structure and Function (CACNA), Fig. 2

Evolutionary relationship between human voltage-gated calcium channels (CaV). Structural homologies are based on alignments of human channels. HVA high voltage activated, LVA low voltage activated

Voltage-Dependent Gating: Activation, Inactivation, Deactivation

As implied by the name, the open probability of CaV channels is regulated or “gated” by membrane potential. The electrical field within the plasma membrane is “sensed” by displacement of positively charged residues of the S4 transmembrane segment. The macroscopic behavior of CaV currents in whole cell voltage clamp experiments is complex. The CaV channels in a cell can be coordinately induced to conduct divalent ions by sequentially clamping the transmembrane potential to a low value (typically −90 to −110 mV) where “inactivation” is removed, making the channels available to open. From that available state, a rapid membrane depolarization to voltage that exceeds threshold level “activates” channel opening. Some CaV are “high voltage activated” (HVA) meaning that activation requires a large depolarization. In contrast, others are “low voltage activated” (LVA) such that only a small depolarization to more negative membrane potentials is sufficient. Invariably, whether HVA or LVA characterizes the subgroup, channel opening is followed by spontaneous closure to reenter the “inactivated” state. The rate at which channels inactivate is often characteristic of CaV families and subfamilies. Finally, activated channels can be “deactivated” (distinct from inactivation). Deactivation occurs when open channels are induced to close by repolarizing the membrane before the channels have entered the inactivated state. Following deactivation, in contrast to channels in the inactivated state, rapid sequential repolarization-depolarization can activate channel opening. In addition to voltage-dependent gating, CaV can be inhibited or activated by phosphorylation events involving protein kinase C (PKC), cyclic nucleotide–dependent protein kinases (e.g., cGMP-PKG, cAMP-PKA),  MAP kinases, and calmodulin-dependent kinases Camk (Buraei and Yang 2010; Huc et al. 2009).

Channel Pharmacology

Prior to the elucidation of sequence information that led to CaVX.x and α1X designations in Table 1, CaV classification was partially based on electrophysiological study of voltage dependence and kinetics. For example, the L-type channel is high voltage activated (i.e., requires a Large depolarization) and has a slowly inactivating current, thus L- or “Long-lasting” behavior. In contrast, low voltage activated T-type channels (i.e., LVA requiring a small depolarization) rapidly inactivate, thus T- or “Transient” behavior. The “T” of T-type CaV can also be thought of as representing the Tiny conductance of individual channels. Early separation of CaV classes depended on such kinetic information and the efficacy with which pharmaceuticals induce blockade. Probably the best-known and therapeutically exploited agents are the dihydropyridine, phenylalkylamine, and benzothiazepine compounds that provide relatively specific CaV1.x, L-type channel inhibition. Moreover, agonists such as BAYK8644 and FPL64176 serve as L-type channel openers. T-type, CaV3.x channels are relatively insensitive to those agents. Modifications of structure to generate compounds such as mibefradil, pimozide, and efonidipine have yielded alternate organic compounds that can block T-type channels although none of them are fully specific at high concentrations (Catterall et al. 2005; Kochegarov 2003; Striessnig and Koschak 2008). In many cases, where organic compound specificity is absent or lacking, peptide inhibitors isolated from venoms have filled roles in the study and identification of CaV subfamilies. A non-exhaustive summary of organic agents and venomous peptides that block CaV subclasses is in provided in Table 2.
Voltage-Gated Calcium Channels: Structure and Function (CACNA), Table 2

Voltage-gated calcium channel (CaV) pharmacology

  

Pharmaceutical

Peptide blocker (source; species)

Agonist

CaV1.1-1.4

L-type (HVA)

Dihydroperidine

Phenylakylamine

Benzothiazepines

Calciseptine

(black mamba)

BAYK8644

FPL64176

CaV2.1

P/Q-type (HVA)

Gabapentin

Mibefradil

ω-agatoxin IVA

(funnel web spider)

 

CaV2.2

N-type (HVA)

Gabapentin

ω-conotoxins

(cone snail)

SNX325 (spider)

 

CaV2.3

R-type (HVA)

 

SNX482 (spider)

 

CaV3.1-3.3

T-type (LVA)a

Mibefradil

Pimozide

Efonidipine

Kurtoxin

(scorpion)

 

HVA high voltage activated, LVA low voltage activated

a Fully selective T-type channel blockers have not been identified

Human Disease Associations and Effects of Gene Deletion

CaV subtypes are widely expressed in neural- and extraneural-excitable cells, including myocardium, skeletal muscle, and smooth muscle. In addition, they are variably expressed in a wide variety of other tissues where their functions are often poorly understood. Table 3 provides a summary of known human disease associations and phenotypic effects of gene deletion. These are summarized in following paragraphs.
Voltage-Gated Calcium Channels: Structure and Function (CACNA), Table 3

Voltage-gated calcium channels (CaV), human disease, and murine deficiency. Insights into voltage-gated calcium channel (CaV) function are derived from known human syndromes attributable to mutations. Phenotypes of global knockout or conditional tissue-specific vascular smooth muscle (VSM) knockout mice are listed for comparison

CaV

Gene symbol

Human association

Murine deficiency

1.1

CACNA1S

HPP1, MH

Muscular dysgenesis

1.2

CACNA1C

Timothy syndrome

Brugada syndrome

Embryonic lethality

Conditional VSM: hypotension

1.3

CACNA1D

Deafness, bradycardia

Deafness, bradycardia

1.4

CACNA1F

CSNB2

CORDX3

Aland Island eye disease

Blindness

2.1

CACNA1A

FHM1, EA2, SA6

Dystonia, weakness ataxia

Neurodegeneration

2.2

CACNA1B

NR

Decreased pain response

Enhanced locomotion

Enhanced aggression

2.3

CACNA1E

NR

Impaired spatial memory

Glucose intolerance

3.1

CACNA1G

NR

Enhanced visceral pain

Bradycardia

3.2

CACNA1H

Epilepsy, absence, generalized (association)

Enhanced peripheral pain

Contracted coronary arteries

Myocardial Fibrosis

3.3

CACNA1I

NR

NR

HPP1 hypokalemic periodic paralysis type 1, MH malignant hyperthermia, VSM vascular smooth muscle, CSNB2 congenital stationary night blindness, CORDX3 X-linked cone-rod dystrophy-3, FHM1 familial hemiplegic migraine type 1, EA2 episodic ataxia type 2, SA6 spinocerebellar ataxia type 6, NR not reported

CaV1.x, L-Type Channels: Expression and Disease Association

The CaV1.1 (α1S) L-type voltage-gated calcium channel carries a slowly activating inward current and acts as the voltage sensor for calcium signaling via the type 1  ryanodine receptor (RyR1,  RyR) in skeletal muscle. Association of CaV1.1 with RyR1 in the plasmalemmal junction facilitates rapid Ca2+ release from sarcoplasmic reticulum (SR) stores (Striessnig et al. 2010; Cannon 2010). Hypokalemic period paralysis type 1 (HPP1) is characterized by attacks of weakness or paralysis, often precipitated by stress, temperature change, exercise, or carbohydrate meals. HPP1 has been most frequently traced to neutralizing point mutations of arginine residues within the S4 voltage-sensing region of CaV1.1. It has been proposed that this modification gives rise to an abnormal “gating pore” current when the S4 region is realigned during depolarization. The role of hypokalemia may be related to its ability to reduce conductance of inward rectifier K+ channels Kir (potassium inwardly rectifying channel) favoring a depolarizing shift in membrane. Malignant hyperthermia (MH) is a potentially lethal disorder in which affected individuals develop skeletal muscle contractures, ATP depletion, lactic acidosis, and fever upon exposure to anesthetics or muscle relaxants. The majority of mutations that induce MH are found in the RYR1 SR Ca2+ release channel, but others have been traced to CaV1.1. In the latter case, point mutations within the cytoplasmic region that links repeats III and IV or modifies the inner arginine of I-S4 are at fault. The III-IV linker region couples CaV1.1 to RYR1 and confers voltage sensing. Depolarization-induced conformational changes lead to rapid RYR1-mediated Ca2+ release. In mice, CaV1.1 deficiency is manifest as muscular dysgenesis, an autosomal recessive phenotype that leads to early death of pups by asphyxiation (Striessnig and Koschak 2008).

CaV1.2 (α1C) is a widely expressed channel subject to extensive alternate splicing. It is present in brain, where it is the dominant L-type isoform; in heart, where it conducts Ca2+ during the plateau phase of the action potential; in smooth muscle, where it mediates the Ca2+ entry required for contraction; in neuroendocrine cells, where it is involved in insulin secretion; and in T-lymphocytes, where it affects immunity (Striessnig et al. 2010; Liao and Soong 2010). The relative predominance of separate exons in heart and smooth muscle accounts for variable ability of organic L-type channel blockers to modify contraction and affect heart rate. Gain-of-function and loss-of-function mutations in CaV1.2 underlie human Timothy and Brugada syndromes, respectively (Liao and Soong 2010). Timothy syndrome, previously known as the long QT syndrome, is associated with syndactyly, neurological manifestations such as autism and depression, facial malformations, structural cardiac defects, early death, and predisposition to infection. The gain of function results in prolonged inward current due to slowing of inactivation and thus, enhanced Ca2+ entry through affected channels. It is inherited in an autosomal dominant pattern, as new mutations, or from an affected parent who is mosaic for the channel. Mutation in the mutually exclusive cardiac CaV1.2 exon yields the type 2 variant of Timothy syndrome (TS type 2, TS2) characterized by cardiac arrhythmias and absence of syndactyly. Brugada syndrome arises most often from mutations in the α1 subunit of the NaV1.5 voltage-gated sodium channel NaV (sodium channel, voltage-gated, type V) but can also result from mutations in CaV1.2 α1 or β2b accessory subunits. Brugada patients are prone to sudden death from cardiac arrhythmias and exhibit short QT intervals and elevated ST segments on electrocardiogram. Extracardiac manifestations are generally mild or absent. Complete deletion of CaV1.2 yields embryonic lethality at day 12.5 when it is required to sustain myocardial contraction. As expected, conditional knockout of CaV1.2 from smooth muscle yields hypotension. Conditional knockout of the channel from cerebral cortex and hippocampus leads to loss of spatial memory (Striessnig and Koschak 2008).

Both voltage-dependent inhibition (VDI) and calcium-dependent inhibition (CDI) are characteristics of CaV1.2 behavior. The former is best studied as the spontaneous inactivation that occurs when Ba2+ (rather than Ca2+, which affects CDI) is the current-carrying ion. VDI may depend upon interactions of the pore with the I-II intracellular loop. In calcium signaling, CDI depends upon interactions of Ca2+ ion with the calcium-sensing accessory subunit calmodulin (CaM) that binds to the IQ motif on the C-terminus of the channel (Minor and Findeisen 2010). Thus, CaM acts as an inhibitory sensor of Ca2+ that limits Ca2+ entry. Ba2+ cannot substitute for Ca2+ in CaM binding so that inactivation is prolonged when Ba2+ is charge carrier. Stated another way, with Ba2+, CDI is lost and VDI can be studied in isolation.

CaV1.3 (α1D) is expressed in brain, heart, and retina. The behavior of CaV1.3 is distinct from CaV1.2 in that the former activates more rapidly and at more negative potentials. Moreover, CaV1.3 lacks the calcium-dependent inactivation (CDI) exhibited by CaV1.2 and some other CaV channels. Only recently has a human channelopathy been traced to CaV1.3 manifest as deafness and bradycardia. That phenotype parallels deafness and sinoatrial node dysfunction of CaV1.3 knockout mice (Baig et al. 2011). Deletion of CaV1.3 in the heterozygous state may be without consequence. The homozygous knockout mouse, however, is deaf and bradycardic but viable and fertile (Striessnig and Koschak 2008). Deafness occurs because CaV1.3 is vital to proper function of inner ear hair cells of the cochlea. The associated bradycardia is benign and overcome during exercise (Striessnig and Koschak 2008; Striessnig et al. 2010).

CaV1.4 (α1F) is found in retina and human deficiency leads to X-linked congenital stationary night blindness, type 2 (CSNB2) and its variants, X-linked cone-rod dystrophy-3 (CORDX3), and Aland Island eye disease or Forsius-Eriksson syndrome (Striessnig et al. 2010). The channel is characterized by rapid activation, occurring at relatively low membrane potentials below −40 mV, and slow inactivation which, like CaV1.3, is related to absence of CDI. CSNB2 patients exhibit variable manifestations of decreased visual acuity, particularly in dim light, myopia, and nystagmus. Associated mutations may yield loss of function, gain of function, or abnormalities in gating. Mutations in other proteins such as calcium-binding protein-4 can yield the CSNB2 phenotype. CaV1.4 is involved in control of neurotransmission in retinal photoreceptors (like CaV1.3 in cochlear hair cells). The relatively low voltage-dependent activation threshold of CaV1.3 and CaV1.4 may be vital to enhance their window current (Ca2+ influx related to the membrane potential range over which channels can activate and escape durable inactivation). The window current of CaV1.3 and CaV1.4 probably facilitates tonic neurotransmitter release in cochlear hair cells and retina, respectively. Structurally, absence of CDI results from the presence of an inhibitory domain near the calmodulin-binding site (IQ domain) on the channel C-terminus. Mutation or elimination of that motif can restore CaM-dependent CDI. Moreover, deletion of the inhibitory domain may occur as a normal splice variant in CaV1.3. An autoinhibitory domain of CaV1.2, generated by proteolytic cleavage of the C-terminus, may serve an analogous inhibitory function in cardiac myocytes (Hulme et al. 2006).

CaV2.x, P/Q-, N-, and R-Type Channels: Expression and Disease Association

CaV2.1 (α1A) P/Q-type channels are predominantly expressed in the central nervous system where they are coupled to exocytosis at synapses. Human loss of function is associated with three autosomal dominant disorders: familial hemiplegic migrane type 1 (FHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SA6) (Pietrobon 2010). FHM1 patients suffer from migraine headache with aura along with motor weakness or frank hemiplegia. Severely affected individuals may exhibit seizures, depression of consciousness, confusion, and prolonged weakness. Some FHM1 families exhibit cerebellar atrophy, progressive ataxia, cognitive impairment, and nystagmus. EA2 manifests in early life with symptoms such as episodic ataxia, loss of coordination, dysarthria, vertigo, and nausea. SA6 manifests later in life as progressive ataxia and cerebellar atrophy that associates with expansion of C-terminal polyglutamine repeats of splice variants. P/Q variants have been proposed to confer susceptibility to generalized seizures (Khosravani and Zamponi 2006) Homozygous CaV2.1 deficiency in mice leads to severe forms of neurological dysfunction involving dystonia, weakness, and ataxia (e.g., Tottering mice). The majority of pups do not survive to weaning and progressive decrease in cerebellar volume is associated with loss of Purkinje and granular cells. Heterozygous mice do not suffer similar neurodegeneration (Striessnig and Koschak 2008).

CaV2.2 (α1B), N-type channels are predominantly expressed in the central nervous system and syndromes traced to their deficiency in humans have not been reported. Mice deficient in the α1B subunit are viable and fertile. Reduced responses to some pain stimuli (Kim et al. 2001), enhanced aggression, and enhanced locomotor activity have been documented (Striessnig and Koschak 2008; Nakagawasai et al. 2010).

CaV2.3 (α1E), R-type channels are widely expressed in neuronal tissue, and have also been found in retina, kidney, pancreatic islets, neuroendocrine cells of the GI tract, and spleen. CaV2.3 has several splice variants and is involved in diverse physiological functions, neurotransmitter release, neuronal plasticity, responses to fear and pain, insulin release, and reproduction. Human disorders traceable to α1B mutations have not been reported; however, the channel is believed to be involved in predisposition to seizure and seizure propagation (Weiergraber et al. 2006). These and other CaV isoforms are targeted by many antiepileptic pharmaceuticals. Mice deficient in α1B have been generated and studied extensively. They show altered responses to some forms of noxious stimuli, impaired spatial memory in maze testing, and disturbances in glucose tolerance and insulin release (Striessnig and Koschak 2008).

CaV3.x, T-Type Channels: Expression and Disease Association

CaV3.x, T-type channels are widely expressed in neural and extraneural tissues. Their behavior is generally distinguished from CaV1.x, L-type channels by their low activation thresholds and tendency toward rapid activation and inactivation (CaV3.3 is an arguable exception). They are also distinguished by their lower Ba2+ to Ca2+ conductance ratio, small single channel currents, and insensitivity to dihydropyridines (Huc et al. 2009; Perez-Reyes 2006; Zamponi et al. 2010). Their best-known roles involve pacemaker functions in heart and brain. They are known to be modulated by cyclic nucleotide–dependent protein kinases (PKA, PKC) (Huc et al. 2009).

CaV3.1 (α1G), T-type channels are expressed predominantly in brain, and notably in thalamocortical relay neurons (TRN) where they participate in spike and wave discharges. CaV3.1 has also been reported in diverse tissues such as sinoatrial node, vascular smooth muscle, endothelia, myometrium, preadipocytes, outer hair cells, and testis. Human diseases associated with CaV3.1 have not been reported and murine deficiency yields a viable phenotype without gross abnormalities. CaV3.1 deficiency leads to inability to induce spike and wave discharges in TRN and, when superimposed by cross breeding, renders mouse models of absence seizures resistant to seizure events (Striessnig and Koschak 2008). Loss of CaV3.1 also leads to enhanced visceral pain, loss of T-type currents in sinoatrial node, and bradycardia in freely moving mice.

CaV3.2 (α1H), T-type channels are expressed predominantly in brain, kidney, liver, and heart. In humans, CaV3.2 variants have been associated with susceptibility to absence epilepsy in Chinese Han children. Other human variants have been proposed to increase susceptibility to generalized seizures. Murine homozygous deletion of CaV3.2 yields a viable and fertile phenotype that experiences delayed growth. Interestingly, CaV3.2 deficient mice exhibit constitutively contracted coronary arteries and myocardial fibrosis (Chen et al. 2003). A physical association between CaV3.2 and large conductance calcium-dependent potassium (BKCa) channels in coronary artery was found in wildtype mice but absent in CaV3.2 knockouts. Thus, it is possible that elimination of stimulation of BKCa might underlie enhanced coronary vasomotor tone in CaV3.2−/−. In a manner analogous to increase in visceral pain induced by CaV3.1 deficiency, knockout of CaV3.2 leads to increase in peripheral pain from thermal or mechanical stimuli (Striessnig and Koschak 2008).

CaV3.3 (α1I), T-type channels are expressed in brain and spinal cord with limited expression in adrenal and thyroid. When compared to either CaV3.1 or CaV3.2, CaV3.3 exhibits slower activation and inactivation rates (Huc et al. 2009; Perez-Reyes 2006). Information on its tissue-specific functions is sparse. Neither human disease association nor effects of murine gene deletion have been reported.

Summary

Voltage-gated calcium channels are large complex proteins evolved from ancient origins. Over the last 30 years, enormous progress has been made in their molecular identification (Table 1). Their predominant expression in excitable tissues such as the nervous system, skeletal muscle, and smooth muscle is consistent with regulation of those tissues through modulation of membrane potential and the important role of Ca2+ ions in intracellular calcium signaling. Much information has also been derived from associations between naturally occurring mutations and human disease. The associated gain-of-function and loss-of-function phenotypes that lead to alteration of neuromuscular functions are consistent with their expected roles. In many cases, the diseases are mimicked by effects of targeted murine gene deletions (Table 3). Pharmacological study remains challenging due to lack of selective organic compounds that are capable of blocking conduction of ions through the various subclasses (Table 2). Efforts to identify such compounds through high-throughput screening methods may bridge the gap and lead to new probes of physiological function as well as pharmaceutical antiarrhythmic, antiepileptic, and antihypertensive agents.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Medicine, Division of NephrologyUniversity of MarylandBaltimoreUSA
  2. 2.Department of Medicine, Division of GastroenterologyUniversity of MarylandBaltimoreUSA