Calcium Channels

The voltage-gated calcium channels constitute one group of a superfamily of ion channels that also includes sodium and potassium channels and amongst which exists functional, sequence and topological similarities. These channels are a major route of calcium translocation across the plasma membranes of excitable cells and serve to support multiple functions, including muscle contraction, hormone and neurotransmitter release, cell motility, cell growth and regulation, cell damage and death and finally cell survival.

There are at least six classes of voltage-gated calcium channels that are differentially distributed according to cell type and location and that may be distinguished by electrophysiological, pharmacological and structural characteristics. Several therapeutically effective drugs, including verapamil, nifedipine, diltiazem and second-generation 1,4-dihydropyridine analogs of nifedipine, interact at the L-type channel and are widely used in the treatment of hypertension and certain cardiovascular disorders.

The voltage-gated calcium channel is a hetero-multimer being composed of α1, α2-δ, and β subunits and, for skeletal muscle, the γ subunit. The α1 subunit is the major functional unit of the channel, expressing the permeation and gating functions and, at least in the case of the L-type channels, the drug binding sites. However, the other subunits, notably the β subunit, have significant impact on the expression and electrophysiological characteristics of the channel. Additionally, the α2-δ subunit may also be involved in drug binding, notably for gabapentin. There are 10 α1 subunits (Cav1.1-1.4, formerly α1S, α1C, α1D and α1F; Cav2.1-2.3, formerly α1A, α1B and α1E; Cav3.1-3.3, formerly α1G, α1H and α1I) and four β subunits (β1-4) known with splice variants of each. The α1 subunits are large membrane proteins composed of four homologous domains, I-IV, with each domain composed of six transmembrane helices and a pore region between helices five and six. The S4 segments contain specific arrays of positive charges that are assigned to a voltage-sensing function. The Cav1.2-1.4 genes code for the α-subunits of the L-type channels of the cardiac and neuronal/endocrine types and Cav1.1 codes for the L-type channels of skeletal muscle. The Cav2.1–2.3 genes code for the N-, P/Q and R-type channels. The functional properties and expression of the α subunits are substantially modified by the presence of β subunits. It is likely that channel subclasses are produced by α-β subunit interactions as well as by splice variations. The Cav3.1-3.3 subunits code for the T-type channel, the most recently cloned channel.

Although electrophysiological differences do exist between the channel classes, the most obvious distinctions are between the T- and the other types. T-type channels need only small depolarizations to be activated and are known as low-voltage-activated (LVA) and they deactivate slowly. In contrast, the other classes all require larger depolarizations to be activated and are known as high-voltage-activated (HVA) channels. Although there are electrophysiological distinctions among the HVA channels, they are not sufficiently precise as to permit unambiguous differentiation solely by these criteria. Additionally, it is likely that subclasses of each of these channel types exist with different biophysical properties. At present, pharmacological differentiation is the best route for differentiating the HVA channels.

The L-type channels are well characterized by small synthetic ligands – verapamil, nifedipine and diltiazem – and the T-type channel is described as preferentially blocked by mibefradil, a structurally distinct entity that was in clinical use albeit it was recently withdrawn. All of these entities interact with their channel targets in a voltage-dependent manner, with the greater affinity being exhibited for the open and inactivated states of the channel. The N-, P- and Q-type channels are sensitive to peptide toxins from molluscs and spiders, including the conotoxins and the agatoxins. The conotoxins GVIA and MVIIA interact with the N-type channels with nanomolar potencies; MVIIC interacts with both N and P/Q types and agatoxin IVA interacts selectively with the P/Q types of channel. No small organic ligands are clinically available for other than the L-type channel, although there are a number of experimental compounds for the T- and N-type channels.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Types of Current L T N
Calcium Channels CaV1.1 –€“ 1.4 CaV3.1 –€“ 3.3 CaV2.1 – 2.3
Conductance, pSa ~25 ~8 ~10-20
Activation Threshold High Low High
Deactivation Rate Fast Slow Fast
Inactivation Rate Slow Fast Moderate
Permeation Ba2+ > Ca2+ Ba2+ = Ca2+ Ba2+ > Ca2+
Function E-C coupling CV system
Smooth muscle
Gene expression endocrine cells
Neurotransmitter release (eye and ear)
Cardiac sino atrial node spiking
Repetitive activity in neurons, endocrine cells
Smooth muscle
Neuronal only, Neurotransmitter release
Pharmacologyb  
1,4-Dihydropyridines [activators/antagonists]
(e.g. Bay K 8644 (B133)/
Nimodipine (N149))
Sensitive Insensitive Insensitive
Phenylalkylamines
(e.g. Verapamil (V4629))
Sensitive Insensitive Insensitive
Benzothiazepines
(e.g. Diltiazem (D2521))
Sensitive Insensitive Insensitive
Benzimidazoles
(e.g. Mibefradil (M5441)
Insensitive Sensitive (not selective)c Not Known
ω-Conotoxin GVIA (C9915) Insensitive Insensitive Sensitive
ω-Conotoxin MVIIC (C4188) Insensitive Insensitive Sensitive
ω-Agatoxin IVA (A6719) Insensitive Insensitive Insensitive
ω-Agatoxin IIIA Sensitive Insensitive Sensitive
Calciseptine Sensitive (not skeletal muscle) Insensitive Insensitive
Calcicludine Sensitive (not skeletal muscle) Sensitive Sensitive
Cd2+ block Potent Weak Potent
Ni2+ block Weak Potent Weak
Radioligands of Choice [3H]-cis-(+)-Diltiazem
[3H]-Desmethoxyverapamil
[3H]-PN 200-110 (Isradipine)
Not Known [125I]-ω-Conotoxin MVIIA
[125]-ω-Conotoxin GVIA
[125I]-ω-Conotoxin MVIIC
Tissue Expression Widespread: CV system, neurons,
endocrine, skeletal muscle
Neurons, smooth muscle, SA node Neurons
Disease Relevance Hypertension
Angina
Cardiac arrhythmias
Malignant hyperthermia
Hypokalemic periodic paralysis
Congenital night blindness
Arrhythmias
Epilepsy
Fertility
Pain

 

 

Types of Current P Q R
Calcium Channels CaV2.1 –€“ 2.3 CaV2.1 –€“ 2.3 CaV2.1 –€“ 2.3
Conductance, pSa ~9-19 16  
Activation Threshold High High High
Deactivation Rate Fast Fast Fast
Inactivation Rate Very slow Moderate Fast
Permeation Ba2+ > Ca2+ Ba2+ > Ca2+ Ba2+ = Ca2+
Function Neuronal only, Neurotransmitter release
Neuronal only, Neurotransmitter release
Neuronal only, Neurotransmitter release
Pharmacologyb  
1,4-Dihydropyridines [activators/antagonists]
(e.g. Bay K 8644 (B133)/
Nimodipine (N149))
Insensitive Insensitive Insensitive
Phenylalkylamines
(e.g. Verapamil (V4629))
Insensitive Not Known Insensitive
Benzothiazepines
(e.g. Diltiazem (D2521))
Insensitive Not Known Insensitive
Benzimidazoles
(e.g. Mibefradil (M5441)
Not Known Not Known Not Known
ω-Conotoxin GVIA (C9915) Insensitive Insensitive Insensitive
ω-Conotoxin MVIIC (C4188) Sensitive Sensitive Sensitive
ω-Agatoxin IVA (A6719) Sensitive Sensitive Insensitive
ω-Agatoxin IIIA Insensitive Sensitive Sensitive
Calciseptine Insensitive Insensitive Insensitive
Calcicludine Sensitive Sensitive Sensitive
Cd2+ block Potent Potent Potent
Ni2+ block Intermediate Potent Potent
Radioligands of Choice Not Known Not Known Not Known
Tissue Expression Neurons Neurons Neurons
Disease Relevance Epilepsy, Migraine
Epilepsy, Migraine
Diabetes

 

Footnotes

a) ~l00 mM Ba2+ as charge carrier.

b) Sensitive refers to concentrations < 1 µM; insensitive refers to concentrations > 1 µM.

c) Mibefradil is not very selective for T-type currents; ethosuximide (E7138) and congeners maybe more selective, although of lower affinity.

 

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References