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OtherIUPHAR Compendium of Voltage-Gated Ion Channels 2005

International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels

William A. Catterall, Edward Perez-Reyes, Terrance P. Snutch and Joerg Striessnig
Pharmacological Reviews December 2005, 57 (4) 411-425; DOI: https://doi.org/10.1124/pr.57.4.5

Article Figures & Data

Figures

  • Fig. 1.
    Fig. 1.

    Subunit structure of CaV1 channels. The subunit composition and structure of calcium channels purified from skeletal muscle are illustrated. The model is updated from the original description of the subunit structure of skeletal muscle calcium channels. This model fits available biochemical and molecular biological results for other CaV1 channels and for CaV2 channels. Predicted α helices are depicted as cylinders. The lengths of lines correspond approximately to the lengths of the polypeptide segments represented.

  • Fig. 2.
    Fig. 2.

    Sequence similarity of voltage-gated calcium channel α1 subunits. Phylogenetic representation of the primary sequences of the calcium channels. Only the membrane-spanning segments and pore loops (∼350 amino acids) are compared. First, all sequence pairs were compared, which clearly defines three subfamilies with intrafamily sequence identities above 80% (CaV1, CaV2, and CaV3). Then a consensus sequence was defined for each subfamily, and these three sequences were compared to one another, with intersubfamily sequence identities of ∼52% (CaV1 vs. CaV2) and 28% (CaV3 vs. CaV1 or CaV2).

Tables

  • 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
    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; spinal cord; adrenal gland; mast cells Dihydropyridines; phenylalkylamines; benzothiazepines 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 calcium 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
  • TABLE 2

    CaV1.1 channels

    Channel name Cav1.1
    Description Voltage-gated calcium channel α1-subunit
    Other names α1s, skeletal muscle L-type Ca2+ channel, skeletal muscle dihydropyridine receptor
    Molecular information Human: 1873aa, L33798 (PMID: 7713519), chr0.1q32, CACNA1S, LocusID: 779
    Rat: 1146aa (partial sequence), L04684 (PMID: 1335956), chr. 13, Cacna1s, LocusID: 116652
    Mouse: 1861aa, L06234 (PMID: 1281468), chr. 1, Cacna1s, LocusID: 12292 (see `Comments')
    Associated subunits α2δ, β, γ1,2
    Functional assays Patch-clamp (whole-cell, single-channel), calcium imaging, gating charge movement, skeletal muscle contraction
    Current ICa,L
    Conductance 13—17pS (in 90—110 mM Ba2+)3,4
    Ion selectivity Ca2+ > Sr2+ > Mg2+ > Ba2+5
    Activation Va = 8—14 mV, τa > 50 ms at +10 mV (10 mM Ca2+)4,6
    Inactivation Vh = —8 mV, 40% current inactivation after 5 s (—5 mV)4
    Activators BayK8644, dihydropyridine agonists, FPL641762,8,9
    Gating modifiers Dihydropyridine antagonists (e.g., (+)- isradipine; IC50 = 13 nM at —90 mV and 0.15 nM at —65 mV)9
    Blockers Nonselective: cadmium (IC50 < 0.5 mM)9; selective for Cav1.x: verapamil, devapamil (IC50 < 1 μM) and other phenylalkylamines, (+)-cis-diltiazem (IC50 < 80 μM)9
    Radioligands (+)-[3H]isradipine (Kd = 0.2—0.7 nM) and other dihydropyridines; (—)-[3H]devapamil (Kd = 2.5 nM), (+)-cis-[3H]diltiazem (Kd = 50 nM)2
    Channel distribution Skeletal muscle transverse tubules (tetramers)10
    Physiological functions Excitation-contraction coupling and Ca2+ homeostasis in skeletal muscle11
    Mutations and pathophysiology Point mutations cause hypokalemic periodic paralysis and malignant hyperthermia susceptibility in humans and muscular dysgenesis in mice (mdg / mdg)12,13
    Pharmacological significance Not established
    Comments The gene for Cav1.1 was first isolated and characterized in rabbit (1873aa, M23919, X05921); several groups reported three-dimensional structures of the purified skeletal muscle calcium channel complex determined using electron cryomicroscopy and single-particle averaging14

    • aa, amino acids; chr., chromosome; Bay K8644, methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carbo xylate; FPL64176, methyl 2,5 dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate.

    • ↵1. Takahashi M, Seagar MJ, Jones JF, Reber BF, and Catterall WA (1987) Subunit structure of dihydropyridine-sensitive calcium channels from skeletal muscle. Proc Natl Acad Sci USA 84:5478-5482

    • ↵2. Glossmann H and Striessnig J (1990) Molecular properties of calcium channels. Rev Physiol Biochem Pharmacol 114:1-105

    • ↵3. Dirksen RT, Nakai J, Gonzales A, Imoto K, and Beam KG (1997) The S5-S6 linker of repeat I is a critical determinant of L-type Ca2+ channel conductance. Biophys J 73:1402-1409

    • ↵4. Freise D, Held B, Wissenbach U, Pfeifer A, Trost C, Himmerkus N, Schweig U, Freichel M, Biel M, Hoffmann F, et al. (2000) Absence of the γ subunit of the skeletal muscle dihydropyridine receptor increases L-type calcium currents and alters channel inactivation properties. J Biol Chem 275:14476-14481

    • ↵5. Pizarro G, Fitts R, Uribe I, and Rios E (1989) The voltage-sensor of excitation-contraction coupling in skeletal muscle: ion dependence and selectivity. J Gen Physiol 94:405-428

    • ↵6. Dirksen RT and Beam KG (1995) Single calcium channel behavior in native skeletal muscle. J Gen Physiol 105:227-247

    • ↵7. Rovnyak GC, Kimball SD, Beyer B, Cucinotta G, DiMarco JD, Gougoutas J, Hedberg A, Malley M, McCarthy JP, Zhang R, et al. (1995) Calcium entry blockers and activators: conformational and structural determinants of dihydropyrimidine calcium channel modulators. J Med Chem 38:119-129

    • ↵8. Striessnig J (1999) Pharmacology, structure and function of cardiac L-type Ca2+ channels. Cell Physiol Biochem 9:242-269

    • ↵9. Glossmann H and Striessnig J (1988) Ca2+ channels. Vitam Horm 44:155-328

    • ↵10. Flucher BE and Franzini-Armstrong C (1996) Formation of junctions involved in excitation-contraction coupling in skeletal and cardiac muscle. Proc Natl Acad Sci USA 93:8101-8106

    • ↵11. Rios E, Pizarro G, and Stefani E (1992) Charge movement and the nature of signal transduction in skeletal muscle excitation-contraction coupling. Annu Rev Physiol 54:109-133

    • ↵12. CACNA1S; Online Mendelian Inheritance in Man (OMIM) no. 114208

    • ↵13. Striessnig J, Hoda JC, Koschak A, Zaghetto F, Mullner C, Sinnegger-Brauns MJ, Wild C, Watschinger K, Trockenbacher A, and Pelster G (2004) L-type Ca2+ channels in Ca2+ channelopathies. Biochem Biophys Res Commun 322:1341-1346

    • ↵14. Wang MC, Dolphin A, and Kitmitto A (2004) L-type voltage-gated calcium channels: understanding function through structure. FEBS Lett 564:245-250

  • TABLE 3

    CaV1.2 channels

    Channel name CaV1.2
    Description Voltage-gated calcium channel α1 subunit
    Other names α1C, cardiac or smooth muscle L-type Ca2+ channel, cardiac or smooth muscle dihydropyridine receptor
    Molecular information Human: 2169aa, L29529 (cardiac; PMID: 8392192), 2138aa, Z34815 (fibroblast; PMID: 1316612); 2138aa, AF465484 (jejunum; PMID: 12176756); chr. 12p13.3, CACNA1C, LocusID: 775
    Rat: 2169aa, M59786 (aortic smooth muscle; PMID: 2170396); 2140/2143aa, M67516/M67515 (brain; PMID: 1648941); chr. 4q42, Cacna1c, LocusID: 24239
    Mouse: 2139aa, L01776 (brain; PMID: 1385406); chr. 6, Cacna1c, LocusID: 12288 (see `Comments')
    Associated subunits α2δ, β, γ1,2
    Functional assays Patch-clamp (whole-cell, single-channel), calcium imaging, cardiac or smooth muscle contraction hormone secretion
    Current ICa,L
    Conductance Ba2+ (25pS) > Sr2+ = Ca2+ (9pS)3
    Ion selectivity Ca2+ > Sr2+ > Ba2+ ≫ Mg2+ from permeability ratios
    Activation Va = —17 mV (in 2 mM Ca2+; HEK cells)4; —4 mV (in 15 mM Ba2+; HEK cells) to —18.8 mV (in 5 mM Ba2+; HEK cells and Xenopus oocytes)5,6,7; τa = 1 ms at +10 mV5
    Inactivation Vh = —50 to —60 mV (in 2 mM Ca2+; HEK cells),4 —18 to —42 mV (in 5—15 mM Ba2+; HEK cells)5,7,8,9; τfast = 150 ms, τslow = 1100 ms; 61% inactivated after 250 ms in HEK cells8 (at Vmax in 15 mM Ba2+)4; ∼70% inactivation after 1 s (at Vmax in 2 mM Ca2+)4; inactivation is accelerated with Ca2+ as charge carrier (calcium-dependent inactivation: 86% inactivated after 250 ms8,10)
    Activators BayK8644, dihydropyridine agonists, FPL6417610,11
    Gating modifiers Dihydropyridine antagonists (e.g., isradipine, IC50 = 7 nM at —60 mV; nimodipine, IC50 = 139 nM at —80 mV)6,9
    Blockers Nonselective: Cd2+12; selective for CaV1.x: devapamil (IC50 = 50 nM in 10 mM Ba2+ at —60 mV) and other phenylalkylamines; diltiazem (IC50 = 33 μM in 10 mM Ba2+ at —60 mV and 0.05Hz)12
    Radioligands (+)-[3H]isradipine (Kd < 0.1 nM) and other dihydropyridines; (—)-[3H]devapamil (Kd = 2.5 nM), (+)-cis-[3H]diltiazem (Kd = 50 nM)11
    Channel distribution Cardiac muscle, smooth muscle (including blood vessels, intestine, lung, uterus); endocrine cells (including pancreatic β-cells, pituitary); neurones13; subcellular localization: concentrated on granule-containing side of pancreatic β-cells14; neurons (preferentially somatodendritic)15
    Physiological functions Excitation-contraction coupling in cardiac or smooth muscle, action potential propagation in sinoatrial and atrioventricular node, synaptic plasticity, hormone (e.g., insulin) secretion10,13,16,17
    Mutations and pathophysiology Required for normal embryonic development (mouse, zebrafish)18,19; de novo G406R mutation in alternative exon 8A in 1 allele causes Timothy syndrome20
    Pharmacological significance Mediates cardiovascular effects of clinically used Ca2+ antagonists17; high concentrations of dihydropyridines exert antidepressant effects through Cav1.2 inhibition17
    Comments Tissue-specific splice variants exist—in addition to cardiac channels, smooth muscle and brain channels have been cloned7,21,22; the gene for Cav1.2 was first isolated and characterized in rabbit heart (2171aa, P15381, X15539)

    • aa, amino acids; chr., chromosome; HEK, human embryonic kidney.

    • ↵1. Cooper CL, Vandaele S, Barhanin J, Fosset M, Lazdunski M, and Hosey MM (1987) Purification and characterization of the dihydropyridine-sensitive voltage-dependent calcium channel from cardiac tissue. J Biol Chem 262:509-512

    • ↵2. Reimer D, Huber IG, Garcia ML, Haase H, and Striessnig J (2000) Beta subunit heterogeneity of L-type calcium channels in smooth muscle tissues. FEBS Lett 467:65-69

    • ↵3. Tsien RW, Hess P, McCleskey EW, and Rosenberg RL (1987) Calcium channels: mechanisms of selectivity, permeation, and block. Annu Rev Biophys Biophys Chem 16:265-290

    • ↵4. Hu H and Marban E (1998) Isoform-specific inhibition of L-type calcium channels by dihydropyridines is independent of isoform-specific gating properties. Mol Pharmacol 53:902-907

    • ↵5. Koschak A, Reimer D, Huber I, Grabner M, Glossmann H, Engel J, and Striessnig J (2001) α1D (Cav1.3) subunits can form L-type calcium channels activating at negative voltages. J Biol Chem 276:22100-22106

    • ↵6. Xu W and Lipscombe D (2001) Neuronal Cav1.3 α1 L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. J Neurosci 21:5944-5951

    • ↵7. Tang ZZ, Liang MC, Lu S, Yu D, Yu CY, Yue DT, and Soong TW (2004) Transcript scanning reveals novel and extensive splice variations in human l-type voltage-gated calcium channel, Cav1.2 α1 subunit. J Biol Chem 279:44335-44343

    • ↵8. Koschak A, Reimer D, Walter D, Hoda JC, Heinzle T, Grabner M, and Striessnig J (2003) Cav1.4 α1 subunits can form slowly inactivating dihydropyridine-sensitive L-type Ca2+ channels lacking Ca2+-dependent inactivation. J Neurosci 23:6041-6049

    • ↵9. Peterson BZ, Johnson BD, Hockerman GH, Acheson M, Scheuer T, and Catterall WA (1997) Analysis of the dihydropyridine receptor site of L-type calcium channels by alanine-scanning mutagenesis. J Biol Chem 272:18752-18758

    • ↵10. Striessnig J (1999) Pharmacology, structure and function of cardiac L-type calcium channels. Cell Physiol Biochem 9:242-269

    • ↵11. Glossmann H and Striessnig J (1990) Molecular properties of calcium channels. Rev Physiol Biochem Pharmacol 114:1-105

    • ↵12. Hockerman GH, Johnson BD, Abbott MR, Scheuer T, and Catterall WA (1997) Molecular determinants of high affinity phenylalkylamine block of L-type calcium channels in transmembrane segment IIIS6 and the pore region of the alpha1 subunit. J Biol Chem 272:18759-18765

    • ↵13. Catterall WA (2001) Structure and regulation of voltage-gated calcium channels. Annu Rev Cell Dev Biol 16:521-555

    • ↵14. Bokvist K, Eliasson L, Ämmälä C, Renstrom E, and Rorsman P (1995) Co-localization of L-type calcium channels and insulin-containing secretory granules and its significance for the initiation of exocytosis in mouse pancreatic B-cells. EMBO J 14:50-57

    • ↵15. Hell JW, Westenbroek RE, Warner C, Ahlijanian MK, Prystay W, Gilbert MM, Snutch TP, and Catterall WA (1993) Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel alpha 1 subunits. J Cell Biol 123:949-962

    • ↵16. Sinnegger-Brauns MJ, Hetzenauer A, Huber IG, Renstrom E, Wietzorrek G, Berjukov S, Cavalli M, Walter D, Koschak A, Waldschutz R, et al. (2004) Isoform-specific regulation of mood behavior and pancreatic β-cell and cardiovascular function by L-type Ca2+ channels. J Clin Investig 113:1430-1439

    • ↵17. Schulla V, Renstrom E, Feil R, Feil S, Franklin I, Gjinovci A, Jing XJ, Laux D, Lundquist I, Magnuson MA, et al. (2003) Impaired insulin secretion and glucose tolerance in β-cell-selective Cav1.2 Ca2+ channel null mice. EMBO J 22:3844-3854

    • ↵18. Seisenberger C, Specht V, Welling A, Platzer J, Pfeifer A, Kuhbandner S, Striessnig J, Klugbauer N, Feil R, and Hofmann F (2000) Functional embryonic cardio-myocytes after disruption of the L-type αC (Cav1.2) calcium channel gene in the mouse. J Biol Chem 275:39193-39199

    • ↵19. Rottbauer W, Baker K, Wo ZG, Mohideen MA, Cantiello HF, and Fishman MC (2001) Growth and function of the embryonic heart depend upon the cardiac-specific L-type calcium channel α1 subunit. Dev Cell 1:265-275

    • ↵20. CACNA1C; OMIM no. 114205

    • ↵21. Snutch TP, Tomlinson WJ, Leonard JP, and Gilbert MM (1991) Distinct calcium channels are generated by alternative splicing and are differentially expressed in the mammalian CNS. Neuron 7:45-57

    • ↵22. Welling A, Ludwig A, Zimmer S, Klugbaue r N, Flockerzi V, Hofmann F (1997) Alternatively spliced IS6 segments of the α1C gene determine the tissue-specific dihydropyridine sensitivity of cardiac and vascular smooth muscle L-type calcium channels. Circ Res 81:526-532

  • TABLE 4

    CaV1.3 channels

    Channel name CaV1.3
    Description Voltage-gated calcium channel α1 subunit
    Other names α1D, “neuroendocrine” L-type Ca2+ channel
    Molecular information Human: 2161aa, M76558 (brain; PMID: 1309651); 2181aa, M83566 (pancreatic β-cells; PMID: 1309948); chr. 3p14.3, CACNA1D, LocusID: 776
    Rat: 1646aa, M57682 (brain; PMID: 1648940); 2203aa, D38101 (pancreatic β-cells; PMID: 7760845); chr. 16p16, Cacna1d, LocusID: 29716
    Mouse: 2144aa, AJ437291 (embryonic heart; PMID: 12900400); chr. 14, Cacna1d, LocusID: 12289 (see “Comments”)
    Associated subunits Most likely at least α2, β, and δ subunits
    Functional assays Patch-clamp (whole-cell, single-channel), calcium imaging
    Current ICa,L
    Conductance Not established
    Ion selectivity Not established
    Activation Va = —15 to —20 mV (mouse cochlear hair cells; 10 mM Ba2+)1,2; —18 mV (in 15 mM Ba2+; HEK cells) to —37 mV (5 mM Ba2+; 2 mM Ca2+ HEK cells or Xenopus oocytes)3,4; τa < 1 ms at +10 mV3
    Inactivation Vh = —36 to —43 mV3,5; τfast = 190 ms, τslow = 1700 ms (at Vmax in HEK cells)3; calcium-induced inactivation is observed after expression in HEK cells3 and in cochlear outer hair cells but not in inner hair cells2
    Activators BayK86441,2,3,4,5
    Gating modifiers Dihydropyridine antagonists (e.g., isradipine, IC50 = 30 nM at —50 mV and 300 nM at —90 mV; nimodipine, IC50 = 3 μM at —80 mV)3,4
    Blockers Nonselective: Cd2+5
    Radioligands (+)-[3H]isradipine (Kd < 0.5 nM)3; in radioreceptor assays, HEK cell-expressed Cav1.2 and Cav1.3 channels bind (+)-[3H]isradipine with indistinguishable KD3; in functional experiments, however, Cav1.2 channels show higher DHP sensitivity—this discrepancy is explained by the slower inactivation of Cav1.3 decreasing the availability of inactivated channels for state-dependent DHP block
    Channel distribution Sensory cells (photoreceptors, cochlear hair cells1,2), endocrine cells (including pancreatic β-cells, pituitary, adrenal chromaffin cells, pinealocytes),7,8,9 low density in heart (atrial muscle, sinoatrial and atrioventricular node)1,7,10 and vascular smooth muscle7; neurones6; subcellular localization: on neurones preferentially located on proximal dendrites and cell bodies6
    Physiological functions Neurotransmitter release in sensory cells, control of cardiac rhythm and atrioventricular node conductance at rest,1,10,12 mood behavior,12 hormone secretion
    Mutations and pathophysiology Deafness, sinoatrial and atrioventricular node dysfunction,1,10,12 no convincing evidence for contribution to pancreatic β-cell L-type currents and insulin secretion in mouse models1,12,13
    Pharmacological significance Hypothetical drug targets for modulators of heart rate,1 antidepressant drugs10 and drugs for hearing disorders1
    Comments Tissue-specific and developmental (exon 1b) splice variants exist—in addition to brain, pancreatic β-cell and cochlear variants have been cloned; it is likely that Cav1.3 channels form most of the so-called `low-voltage-activated' L-type currents found in the brain and sinoatrial node, although some splice variants of Cav1.2 can also activate at more negative potentials

    • aa, amino acids; chr., chromosome; HEK, human embryonic kidney; DHP, dihydropyridine.

    • ↵1. Platzer J, Engel J, Schrott-Fischer A, Stephan K, Bova S, Chen H, Zheng H, and Striessnig J (2000) Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type calcium channels. Cell 102:89-97

    • ↵2. Michna M, Knirsch M, Hoda JC, Muenkner S, Langer P, Platzer J, Striessnig J, and Engel J (2003) Cav1.3 (α1D) Ca2+ currents in neonatal outer hair cells of mice. J Physiol 553:747-758

    • ↵3. Koschak A, Reimer D, Huber I, Grabner M, Glossmann H, Engel J, and Striessnig J (2001) α1D (Cav1.3) subunits can form L-type calcium channels activating at negative voltages. J Biol Chem 276:22100-22106

    • ↵4. Xu W and Lipscombe D (2001) Neuronal Cav1.3α1 L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. J Neurosci 21:5944-5951

    • ↵5. Scholze A, Plant TD, Dolphin AC, and Nürnberg B (2001) Functional expression and characterization of a voltage-gated Cav1.3 (α1D) calcium channel subunit from an insulin-secreting cell line. Mol Endocrinol 15:1211-1221

    • ↵6. Hell JW, Westenbroek RE, Warner C, Ahlijanian MK, Prystay W, Gilbert MM, Snutch TP, and Catterall WA (1993) Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel α1 subunits. J Cell Biol 123:949-962

    • ↵7. Takimoto K, Li D, Nerbonne JM, and Levitan ES (1997) Distribution, splicing and glucocorticoid-induced expression of cardiac α1C and α1D voltage-gated calcium channel mRNAs. J Mol Cell Cardiol 29:3035-3042

    • ↵8. Garcia-Palomero E, Renart J, Andres-Mateos E, Solis-Garrido LM, Matute C, Herrero CJ, Garcia AG, and Montiel C (2001) Differential expression of calcium channel subtypes in the bovine adrenal medulla. Neuroendocrinology 74:251-261

    • ↵9. Chik CL, Liu QY, Li B, Klein DC, Zylka M, Kim DS, Chin H, Karpinski E, and Ho AK (1997) Alpha 1D L-type Ca2+-channel currents: inhibition by a beta-adrenergic agonist and pituitary adenylate cyclase-activating polypeptide (PACAP) in rat pinealocytes. J Neurochem 68:1078-1087

    • ↵10. Mangoni ME, Couette B, Bourinet E, Platzer J, Reimer D, Striessnig J, and Nargeot J (2003) Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity. Proc Natl Acad Sci USA 100:5543-5548

    • ↵11. Namkung Y, Skrypnyk N, Jeong MJ, Lee T, Lee MS, Kim HL, Chin H, Suh PG, Kim SS, and Shin HS (2001) Requirement for the L-type calcium channel α1D subunit in postnatal pancreatic beta cell generation. J Clin Investig 108:1015-1022

    • ↵12. Sinnegger-Brauns MJ, Hetzenauer A, Huber IG, Renstrom E, Wietzorrek G, Berjukov S, Cavalli M, Walter D, Koschak A, Waldschutz R, et al. (2004) Isoform-specific regulation of mood behavior and pancreatic β-cell and cardiovascular function by L-type Ca2+ channels. J Clin Investig 113:1430-1439

    • ↵13. Schulla V, Renstrom E, Feil R, Feil S, Franklin I, Gjinovci A, Jing XJ, Laux D, Lundquist I, Magnuson MA, et al. (2003) Impaired insulin secretion and glucose tolerance in beta cell-selective Cav1.2 Ca2+ channel null mice. EMBO J 22:3844-3854

  • TABLE 5

    CaV1.4 channels

    Channel name Cav1.4
    Description Voltage-gated calcium channel α1 subunit
    Other names α1F
    Molecular information Human: 1966aa, AJ224874 (PMID: 9662399); chr. Xp11.23, CACNA1F, LocusID: 778
    Rat: 1981aa, AF365975 (PMID: 11526344); chr. Xq22, Cacna1f, LocusID: 114493
    Mouse: 1985aa, AF192497 (PMID: 10873387); chr. X, Cacna1f, LocusID: 54652
    Associated subunits Not established; preliminary functional evidence for β2 association in retinal neurons1
    Functional assays Patch-clamp (whole-cell, single-channel), calcium imaging
    Current ICa,L
    Conductance Preliminary evidence for very small single channel conductance (less than half of Cav1.2); Ba2+ > Ca2+2,4,6
    Ion selectivity Not established
    Activation Va = -2.5 to -12 mV (2–20 mM Ca2+ or 15–20 mM Ba2+; HEK cells)3,4,5,6; τa < 1 ms at Vmax (but slower components were also observed)3,6
    Inactivation Vh = -9 to -27 mV (10–20 mM Ba2+, HEK cells)4,6; inactivation kinetics even slower than those of Cav1.3 with incomplete inactivation during 10-s depolarizations to Vmax3; calcium-induced inactivation is not observed for Cav1.4 channels expressed in HEK cells3,4,6 but after expression in Xenopus oocytes2
    Activators BayK86442,3,4,6
    Gating modifiers Dihydropyridine antagonists: nifedipine (IC50 = 944 nM at - 100 mV, ∼300 nM at -50 mV4; isradipine: ∼80% inhibition by 100 nM at -50 mV3,6 and 1 μM at -90 mV)3; d-cis-diltiazem (IC50=92 μM); verapamil: 69% inhibition at 100 μM (0.2 Hz, holding potential = -80 mV)6
    Blockers Nonselective: Cd2+2
    Radioligands Unlike for Cav1.2 and Cav1.3, no high-affinity (+)-[3H]isradipine binding detectable (HEK cells) (J. Striessnig, unpublished observations)
    Channel distribution Retinal photoreceptors and bipolar cells, spinal cord, lymphoid tissue (plasma and mast cells)1,4,7,8,9,10
    Physiological functions Neurotransmitter release in retinal cells
    Mutations and pathophysiology Mutations cause X-linked congenital stationary night blindness type 27,9,11,12
    Pharmacological significance Not established
    Comments The biophysical properties of heterologously expressed Cav1.4 channels resemble those recorded in retinal neurons, suggesting that this channel type underlies retinal ICa,L–however, similar to Cav1.4, Cav1.3 channels also inactivate slowly and activate rapidly and may therefore also contribute to retinal ICa,L

    • aa, amino acids; chr., chromosome; HEK, human embryonic kidney.

    • ↵1. Ball SL, Powers PA, Shin HS, Morgans CW, Peachey NS, and Gregg RG (2002) Role of the β2 subunit of voltage-dependent calcium channels in the retinal outer plexiform layer. Investig Ophthalmol Vis Sci 43:1595-1603

    • ↵2. Hoda JC, Zaghetto F, Koschak A, and Striessnig J (2005) CSNB2 mutations S229P, G369D, L1068P, and W1440X alter channel gating or functional expression of Cav1.4 L-type Ca2+ channels. J Biol Chem 25:252-259

    • ↵3. Koschak A, Reimer D, Walter D, Hoda JC, Heinzle T, Grabner M, and Striessnig J (2003) Cav1.4 α1 subunits can form slowly in activating dihydropyridine-sensitive L-type Ca2+ channels lacking Ca2+-dependent inactivation. J Biol Chem 23:6041-6049

    • ↵4. McRory JE, Hamid J, Doering CJ, Garcia E, Parker R, Hamming K, Chen L, Hildebrand M, Beedle AM, Feldcamp L, et al. (2004) The CACNA1F gene encodes an L-type calcium channel with unique biophysical properties and tissue distribution. J Biol Chem 24:1707-1718

    • ↵5. Haeseleer F, Imanishi Y, Maeda T, Possin DE, Maeda A, Lee A, Rieke F, and Palczewski K (2004) Essential role of Ca2+-bindingprotein 4, a Cav1.4 channel regulator, in photoreceptor synaptic function. Nat Neurosci 7:1079-1087

    • ↵6. Baumann L, Gerstner A, Zong X, Biel M, and Wahl-Schott C (2004) Functional characterization of the L-type Ca2+ channel Cav1.4 α1 from mouse retina. Investig Ophthalmol Vis Sci 45:708-713

    • ↵7. Bech-Hansen NT, Naylor MJ, Maybaum TA, Pearce WG, Koop B, Fishman GA, Mets M, Musarella MA, and Boycott KM (1998) Loss-of-function mutations in a calcium-channel α1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nat Genet 19:264-267

    • ↵8. Naylor MJ, Rancourt DE, and Bech-Hansen NT (2000) Isolation and characterization of a calcium channel gene, Cacna1f, the murine orthologue of the gene for incomplete X-linked congenital stationary night blindness. Genomics 66:324-327

    • ↵9. Strom TM, Nyakatura G, Apfelstedt-Sylla E, Hellebrand H, Lorenz B, Weber BH, Wutz K, Gutwillinger N, Ruther K, Drescher B, et al. (1998) An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nat Genet 19:260-263

    • ↵10. Firth SI, Morgan IG, Boelen MK, and Morgans CW (2001) Localization of voltage-sensitive L-type calcium channels in the chicken retina. Clin Experiment Ophthalmol 29:183-187

    • ↵11. CACNA1F; OMIM no. 300110

    • ↵12. Striessnig J, Hoda JC, Koschak A, Zaghetto F, Mullner C, Sinnegger-Brauns MJ, Wild C, Watschinger K, Trockenbacher A, and Pelster G (2004) L-type Ca2+ channels in Ca2+ channelopathies. Biochem Biophys Res Commun 322:1341-1346

  • TABLE 6

    CaV2.1 channels

    Channel name Cav2.1
    Description Voltage-gated calcium channel α1 subunit
    Other names α1A, P-type, Q-type, rbA-I (in rat)1; BI-1, BI-2 (in rabbit)2
    Molecular information Human: 2510aa, AF004883, 2662aa, AF004884, chr. 19p13, CACNA1A
    Rat: 2212aa, M64373
    Mouse: 2165aa, NM007578, NP031604
    Rabbit: 2273aa, X57476 (see “Comments”)
    Associated subunits α2δ, β, possibly γ
    Functional assays Voltage-clamp, patch-clamp, calcium imaging, neurotransmitter release
    Current ICa,P, ICa,Q
    Conductance 9, 14, 19pS (P-type, cerebellar Purkinje neurones)4; 16–17pS (for α1A/α2δ/β in Xenopus oocytes)2,5,6
    Ion selectivity Ba2+ > Ca2+
    Activation Va = –5 mV for native P-type, Va = –11 mV for native Q-type (with 5 mM Ba2+ charge carrier)7
    Va = –4.1 mV for rat α1A-a/α2δ/β4
    Va = +2.1 mV for rat α1A-b/α2δ/β4 (with 5 mM Ba2+ charge carrier)6
    Va = +9.5 mV; τa = 2.2 ms at +10 mV for human α1A-1/α2δ/β1b in HEK293 cells (with 15 mM Ba2+ charge carrier)3
    Inactivation Vh = –17.2 mV for α1A-a/α2δ/β4; Vh = –1.6 mV for α1A-b/α2δ/β4 (with 5 mM Ba2+ charge carrier); Vh = –17 mV, τh = 690 ms at +10 mV human α1A-1/α2δ/β1b in HEK293 cells (with 15 mM Ba2+ charge carrier)3; τh > 1 s at 0 mV native P-type (with 5 mM Ba2+ charge carrier)7 (see “Comments”)
    Activators None
    Gating modifiers ω-agatoxin IVA (P-type Kd = 1–3 nM8; Q-type Kd ∼ 100–200 nM5,9), ω-agatoxin IVB6
    Blockers ω-conotoxin MVIIC8; other blockers include piperidines, substituted diphenylbutylpiperidines, piperazines, volatile anesthetics, gabapentin, mibefradil, and peptide toxins DW13.3 and ω-conotoxin SVIB21,22,23,24,25,26 (see “Comments”)
    Radioligands [125I]ω-conotoxin MVIIC
    Channel distribution Neurons (presynaptic terminals, dendrites, some cell bodies), heart, pancreas, pituitary
    Physiological functions Neurotransmitter release in central neurons and neuromuscular junction; excitation-secretion coupling in pancreatic β-cells
    Mutations and pathophysiology Missense mutations in IS4-IS5, IIS4-IIS6, IIIS4-IIIS6, and IVS4-IVS6 cause FHM27; a common feature among FHM mutations is an apparent gain-of-function phenotype as a result of a shift in V50act to more hyperpolarized potentials (an increased probability of opening at the single channel level)28,29; other effects include a decrease in maximal current density at the whole-cell level and alterations of synaptic transmission28,29,30,31; point mutations in IIS1, IIS6-IIIS2, IIIS5-IIIS6, and IVS1-IVS5 cause episodic ataxia type-2, a polyglutamine expansion in the carboxyl region causes spinocerebellar ataxia type-6, and mutation of IS5-IS6 and IVS6 causes episodic and progressive ataxia10,11,12,27
    Pharmacological significance Peptide toxins that selectively inhibit Cav2.1 channel block a significant portion of neurotransmission in the mammalian CNS13; block of Cav2.1 channels inhibits the late-phase formalin response and inflammatory pain but has no significant effect on mechanical allodynia or thermal hyperalgesia14,15,16,17; mice lacking a functional Cav2.1 gene exhibit cerebellar atrophy, severe muscle spasms, and ataxia and usually die by 3 to 4 weeks postnatal18,19
    Comments Rates of inactivation and Vh are differentially affected by coexpression with β1b, β2a, β3, or β4 subunits, as well as by alternative splicing of the α1A subunit; identified regions of alternative splicing include the domain I-II linker, domain II-III linker, IVS3-IVS4, and the carboxyl terminus1,2,6,32,33,34; whole-cell currents with P-type kinetics seem to be conducted by the α1A-b splice variant coexpressed with any of the β subunits or by the α1A-a splice variant coexpressed with the β2a subunit6,7,20; whole-cell currents with Q-type kinetics seem to be encoded by α1A-a coexpressed with any of the β1b, β3, or β4 subunits6,20; whole-cell currents with Q-type pharmacology seem to be encoded by α1A splice variants containing Asp Pro residues in the domain IV S3-S4 linker, whereas whole-cell currents with P-type pharmacology seem to be conducted by α1A splice variants missing Asp Pro residues in IV S3-S4 linker3,6; alternative splicing also alters current density, current-voltage relations, calcium/calmodulin-dependent facilitation, sensitivity to mibefradil, and binding to intracellular synaptic proteins such as Mint1, CASK, syntaxin, and SNAP-2526,32,36

    • aa, amino acids; chr., chromosome; HEK, human embryonic kidney; FHM, familial hemiplegic migraine; CNS, central nervous system.

    • ↵1. Starr TVB, Prystay W, and Snutch TP (1991) Primary structure of a calcium channel that is highly expressed in the rat cerebellum. Proc Natl Acad Sci USA 88:5621-5625

    • ↵2. Mori Y, Friedrich T, Kim MS, Mikami A, Nakai J, Ruth P, Bosse E, Hofmann F, Flockerzi V, Furuichi T, et al. (1991) Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature (Lond) 350:398-402

    • ↵3. Hans M, Urrutia A, Deal C, Brust PF, Stauderman K, Ellis SB, Harpold M, Johnson EC, and Williams ME (1999) Structural elements in domain IV that influence biophysical and pharmacological properties of human α1A-containing high-voltage-activated calcium channels. Biophys J 76:1384-1400

    • ↵4. Llinas R, Sugimori M, Hillman DE, and Cherksey B (1992) Distribution and functional significance of the P-type voltage-dependent calcium channels in the mammalian central nervous system. Trends Neurosci 15:2995-3012

    • ↵5. Sather WA, Tanabe T, Zhang JF, Mori Y, Adams ME, and Tsien RW (1993) Distinctive biophysical and pharmacological properties of class A (BI) calcium channel α1 subunits. Neuron 11:291-303

    • ↵6. Bourinet E, Soong TW, Sutton K, Slaymaker S, Mathews E, Monteil A, Zamponi GW, Nargeot J, and Snutch TP (1999) Splicing of α1A subunit gene generates phenotypic variants of P- and Q-type calcium channels. Nat Neurosci 2:407-415

    • ↵7. Merlestein PG, Foehring RC, Tkatch T, Song WJ, Baranauskas G, and Surmeier JD (1999) Properties of Q-type calcium channels in neostriatal and cortical neurons are correlated with β subunit expression. J Biol Chem 19:7268-7277

    • ↵8. Mintz IM, Venema VJ, Swiderek K, Lee T, Bean BP, and Adams ME (1992) P-type calcium channels blocked by the spider toxin ω-Aga-IVA. Nature (Lond) 355:827-829

    • ↵9. Randall A and Tsien RW (1995) Pharmacological dissection of multiple types of calcium channel currents in rat cerebellar granule neurons. J Biol Chem 15:2995-3012

    • ↵10. Ducros A, Denier C, Joutel A, Vahedi K, Michel A, Darcel F, Madigand M, Guerouaou D, Tison F, Julien J, et al. (1999) Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. Am J Hum Genet 64:89-98

    • ↵11. Kraus RL, Sinnegger MJ, Koschak A, Glossmann H, Stenirri S, Carrera P, and Striessnig J (2000) Three new familial hemiplegic migraine mutants affect P/Q-type calcium channel kinetics. J Biol Chem 275:9239-9243

    • ↵12. Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, et al. (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the calcium channel gene CACNL1A4. Cell 87:543-552

    • ↵13. Dunlap K, Luebke JI, and Turner TJ (1995) Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci 18:89-98

    • ↵14. Chaplan SR, Pogrel JW, and Yaksh TL (1994) Role of voltage-dependent calcium channel subtypes in experimental tactile allodynia. J Pharmacol Exp Ther 269:1117-1123

    • ↵15. Malmberg AB and Yaksh TL (1994) Voltage-sensitive calcium channels in spinal nociceptive processing: blockade of N- and P-type channels inhibits formalin-induced nociception. J Biol Chem 14:4882-4890

    • ↵16. Sluka KA (1997) Blockade of calcium channels can prevent the onset of secondary hyperalgesia and allodynia induced by intradermal injection of capsaicin in rats. Pain 71:157-164

    • ↵17. Sluka KA (1998) Blockade of N- and P/Q-type calcium channels reduces the secondary heat hyperalgesia induced by acute inflammation. J Pharmacol Exp Ther 287:232-237

    • ↵18. Jun K, Piedras-Rentera E, Smith SM, Wheeler DB, Lee SB, Lee TG, Chin H, Adams ME, Scheller RH, Tsien RW, and Shin HS (2000) Ablation of P/Q type calcium channel currents, altered synaptic transmission and progressive ataxia in mice lacking the α1A subunit. Proc Natl Acad Sci USA 96:15245-15250

    • ↵19. Fletcher CF, Tottene A, Lennon VA, Wilson SM, Dubel SJ, Paylor R, Hosford DA, Tessarollo L, McEnery MW, Pietrobon D, et al. (2001) Dystonia and cerebellar atrophy in Cacnl4 null mice lacking P/Q calcium channel activity. FASEB J 15:1288-1290

    • ↵20. Stea A, Tomlinson WJ, Soong TW, Bourinet E, Dubel SJ, Vincent SR, and Snutch TP (1994) Localization and functional properties of a rat brain α1A calcium channel reflect similarities to neuronal Q- and P-type channels. Proc Natl Acad Sci USA 91:10567-10580

    • ↵21. Sah DW and Bean BP (1994) Inhibition of P-type and N-type calcium channels by dopamine receptor antagonists. Mol Pharmacol 45:84-92

    • ↵22. Sutton K. Siok C, Stea A, Zamponi G, Heck SD, Volkmann RA, Ahlijanian MK, and Snutch TP (1998) Inhibition of neuronal calcium channels by a novel peptide spider toxin, DW 13.3. Mol Pharmacol 54:407-418

    • ↵23. Oka M, Itoh Y, Wada M, Yamamoto A, and Fujita T (2003) Gabapentin blocks L-type and P/Q-type Ca2+ channels involved in depolarization-stimulated nitric oxide synthase activity in primary cultures of neurons from mouse cerebral cortex. Pharm Res 20:897-899

    • ↵24. Dooley DJ, Donovan CM, Meder WP, and Whetzel SZ (2002) Preferential action of gabapentin and pregabalin at P/Q-type voltage-sensitive calcium channels: inhibition of K+-evoked [3H]-norepinephrine release from rat neocortical slices. Synapse 45:171-190

    • ↵25. Kamatchi GL, Chan CK, Snutch T, Durieux, and Lynch III C (1999) Volatile anesthetic inhibition of neuronal Ca channel currents expressed in Xenopus oocytes. Brain Res 831:85-96

    • ↵26. Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP, and Nargeot J (2000) Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels. Neuropharmacology 39:1-10

    • ↵27. Lorenzon NM and Beam K (2005) Calcium channelopathies, in Voltage-Gated Calcium Channels (Zamponi G ed) pp 240–261, Kluwer Academic/Plenum Publishers

    • ↵28. Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, and Pietrobon D (2002) Familial hemiplegic migraine mutations increase Ca2+ influx through single human Cav2.1 channels and decrease maximal Cav2.1 current density in neurons. Proc Natl Acad Sci USA. 99:13284-13289

    • ↵29. van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, Broos LA, Cesetti T, van de Ven RC, Tottene A, van der Kaa J, Plomp JJ, et al. (2004) A Cacna1a knock in migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41:701-710

    • ↵30. Cao YQ, Piedras-Renteria ES, Smith GB, Chen G, Harata NC, and Tsien RW (2004) Presynaptic Ca2+ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca2+ channelopathy. Neuron 43:387-400

    • ↵31. Cao Y and Tsien R (2005) Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission. Proc Natl Acad Sci USA 102:2590-2595

    • ↵32. Soong TW, DeMaria CD, Alvania RS, Zweifel LS, Liang MC, Mittman S, Agnew W, and Yue DT (2002) Systematic identification of splice variants inhuman P/Q-type channel α12.1 subunits: implications for current density and Ca2+-dependentinactivation. J Neurosci 22:10142-10152

    • ↵33. Krovetz HS, Helton TD, Crews AL and Horne WA (2000) C-Terminal alternative splicing changes the gating properties of a human spinal cord calcium channel alpha 1A subunit. J Neurosci 20:7564-7570

    • ↵34. Chaudhuri D, Chang SY, DeMaria CD, Alvania RS, Soong TW, and Yue DT (2004) Alternative splicing as a molecular switch for Ca2+/calmodulin-dependent facilitation of P/Q-type Ca2+ channels. J Neurosci 24:6334-6342

    • ↵35. Rettig J, Sheng ZH, Kim DK, Hodson CD, Snutch TP, and Catterall WA (1996) Isoform-specific interaction of the α1A subunits of brain Ca2+ channels with the presynaptic proteins syntaxin and SNAP-25. Proc Natl Acad Sci USA 93:7363-7368

    • ↵36. Maximov A, Sudhof TC, and Bezprozvanny I (1999) Association of neuronal calcium channels with modular adaptor proteins. J Biol Chem 274:24453-24456

  • TABLE 7

    CaV2.2 channels

    Channel name CaV2.2
    Description Voltage-gated calcium channel α1 subunit
    Other names N-type, α1B; rbB-I, rbB-II (in rat),1,2 BIII (in rabbit)3
    Molecular information Human: 2339aa, M94172, 2237aa, M94173,4 chr. 9q34, CACN1B
    Rat: 2336aa, M929051
    Mouse: 2329aa, NM007579, NP031605
    Associated subunits α2δ/β1, β3, β4,5 possibly γ
    Functional assays Voltage-clamp, patch-clamp, calcium imaging, neurotransmitter release, 45Ca uptake into synaptosomes
    Current ICa,N
    Conductance 20pS (bullfrog sympathetic neurones)6; 14.3pS (rabbit BIII cDNA in skeletal muscle myotubes)3
    Ion selectivity Ba2+ > Ca2+
    Activation Va = +7.8 mV, τa = 3 ms at +10 mV (human α1B/α2δ/β1-3 in HEK293 cells, 15 mM Ba2+ charge carrier)4,7; Va = +9.7 mV, τa = 2.8 ms at +20 mV (rat α1B-II/β1b, in Xenopus oocytes, 40 mM Ba2+ charge carrier)2
    Inactivation Vh = –61 mV, τh ∼200 ms at +10 mV (human α1B/α2δ/β1-3 in HEK293 cells, 15 mM Ba2+ charge carrier)4,7; Vh = –67.5 mV; τh = 112 ms at +20 mV (rat α1B-II/β1b in Xenopus oocytes, 40 mM Ba2+)2
    Activators None
    Gating modifiers None
    Blockers ω-conotoxin GVIA (1–2 μM, irreversible block), ω-conotoxin MVIIA (SNX-111, Ziconotide/Prialt), ω-conotoxin MVIIC8; other blockers include piperidines, substituted diphenylbutylpiperidines, long alkyl chain molecules, aliphatic monoamines, tetrandine, gabapentin, peptidylamines, volatile anesthetics, the peptide toxins SNX-325 and DW13.3, as well as the ω-conotoxins SVIA, SVIB, and CVID20,21,22,23,24,25,26,27,28,29,30a,30b,30c,30d,30e,31,32,33,34
    Radioligands [125I]ω-conotoxin GVIA (Kd = 55 pM, human α1B/α2δ/β1-3 in HEK293 cells)4
    Channel distribution Neurons (presynaptic terminals, dendrites, cell bodies)9
    Physiological functions Neurotransmitter release in central and sympathetic neurons10; sympathetic regulation of the circulatory system11,35; activity and vigilance state control36; sensation and transmission of pain (see “Pharmacological significance” and “Comments”)
    Mutations and pathophysiology Differing reports exist: mice lacking a functional CaV2.2 gene exhibit a normal life span and no detectable behavioral modifications compared with wild type but possess an increase in basal mean atrial pressure and other functional alterations to the sympathetic nervous system11–however, in a different study, approximately 1/3 of the mice lacking a functional CaV2.2 gene did not survive to weaning, but surviving animals were normal except for a decrease in anxiety-related behavior and a suppression of inflammatory and neuropathic pain responses12; no point mutations in the native CaV2.2. gene have been reported to date
    Pharmacological significance In rats, intrathecal administration of ω-conotoxin GVIA or ω-conotoxin MVIIA shows strong effects on inflammatory pain, postsurgical pain, thermal hyperalgesia, and mechanical allodynia13,14,15; in humans, intrathecal administration of SNX-111 (Ziconotide/Prialt, synthetic ω-conotoxin MVIIA) to patients unresponsive to intrathecal opiates significantly reduced pain scores and in a number of specific instances resulted in relief after many years of continuous pain16
    Comments In case studies, Ziconotide/Prialt has been examined for usefulness in the management of intractable spasticity following spinal cord injury in patients unresponsive to baclofen and morphine17; side effects of intrathecal administration of Ziconotide/Prialt include nystagmus, sedation, confusion, auditory and visual hallucinations, severe agitation, and unruly behavior18; intravenous administration of Ziconotide to humans results in significant orthostatic hypotension19; identified regions of alternative splicing include the domain I-II linker, domain II-III linker, IIIS3-IIIS4, IVS3-IVS4, and the carboxyl terminus1,2,3,4,37,38,39; splicing affects a number of channel properties, including current-voltage relations and kinetics, and is associated with cell-specific expression–in particular, expression of the e37a splice isoform in dorsal root ganglia correlates with a subset of nociceptive neurons40,41,42; alternative splicing also alters interactions with intracellular synaptic proteins such as Mint1, CASK, syntaxin, and SNAP-2543,44,45

    • aa, amino acid; chr., chromosome; HEK, human embryonic kidney.

    • ↵1. Dubel SJ, Starr TV, Hell J, Ahlijanian MK, Enyeart JJ, Catterall WA, and Snutch TP (1992) Molecular cloning of the α1 subunit of an ω-conotoxin-sensitive calcium channel. Proc Natl Acad Sci USA 89:5058-5062

    • ↵2. Stea A, Dubel SJ, and Snutch TP (1999) α1B N-type calcium channel isoforms with distinct biophysical properties. Ann NY Acad Sci 868:118-130

    • ↵3. Fujita Y, Mynlieff M, Dirksen RT, Kim M, Niidome T, Nakai J, Friedrich T, Iwabe N, Miyata T, Furuichi T, et al. (1993) Primary structure and functional expression of the ω-conotoxin-sensitive N-type calcium channel from rabbit brain. Neuron 10:585-598

    • ↵4. Williams ME, Brust PF, Feldman DH, Patthi S, Simerson S, Maroufi A, McCue AF, Velicelebi G, Ellis SB, and Harpold M (1992) Structure and functional expression of an ω-conotoxin-sensitive human N-type calcium channel. Science 257:389-395

    • ↵5. Scott VE, De Waard M, Liu H, Gurnett CA, Venzke DP, Lennon VA, and Campbell KP (1996) β subunit heterogeneity in N-type calcium channels. J Biol Chem 271:3207-3212

    • ↵6. Elmslie KS (1997) Identification of the single channels that underlie the N-type and L-type calcium currents in bullfrog sympathetic neurons. J Neurosci 17:2658-2668

    • ↵7. Williams ME, Marubio LM, Deal CR, Hans M, Brust PF, Philipson L. Miller RJ, Johnson EC, Harpold MM, and Ellis SB (1994) Structure and functional characterization of neuronal α1E calcium channel subtypes. J Biol Chem 269:22347-22357

    • ↵8. Hillyard DR, Monje VD, Mintz IM, Bean BP, Nadasdi L, Ramachandran J, Miljanich G, Azimi-Zoonooz A, McIntosh JM, Cruz LJ, et al. (1992) A new conus peptide ligand for mammalian presynaptic calcium channels. Neuron 9:9-77

    • ↵9. Westenbroek RE, Hell JW, Warner C, Dubel SJ, Snutch TP, and Catterall W (1992) Biochemical properties and subcellular distribution of an N-type calcium channel α1 subunit. Neuron 6:1099-1115

    • ↵10. Dunlap K, Luebke JI, and Turner TJ (1995) Exocytotic calcium channels in mammalian central neurons. Trends Neurosci 18:9-98

    • ↵11. Ino M, Yoshinaga T, Wakamori M, Miyamoto N, Takahashi E, Sonoda J, Kagaya T, Oki T, Nagasu T, Nishizawa Y, et al. (2001) Functional disorders of the sympathetic nervous system in mice lacking the α1B subunit (CaV2.2) of N-type calcium channels. Proc Natl Acad Sci USA 98:323-5328

    • ↵12. Saegusa H, Kurihara T, Zong S, Kazuno A, Matsuda Y, Nonaka T, Han W, Toriyama H, and Tanabe T (2001) Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type calcium channel. EMBO J 20:2349-2356

    • ↵13. Malmberg AB and Yaksh TL (1994) Voltage-sensitive calcium channels in spinal nociceptive processing: blockade of N- and P-type channels inhibits formalin-induced nociception. J Neurosci 14:4882-4890

    • ↵14. Bowersox SS, Gadbois T, Singh T, Pettus M, Wang Y-X, and Luther RR (1996) Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX-111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain. J Pharmacol Exp Ther 279:1243-1249

    • ↵15. Sluka KA (1998) Blockade of N- and P/Q-type calcium channels reduces the secondary heat hyperalgesia induced by acute inflammation. J Pharmacol Exp Ther 287:232-237

    • ↵16. Vanegas H and Schaible HG (2000) Effects of antagonists to high-threshold calcium channels upon spinal mechanisms of pain, hyperalgesia and allodynia. Pain 85:9-18

    • ↵17. Ridgeway B, Wallace M, and Gerayli A (2000) Ziconotide for the treatment of severe spasticity after spinal cord injury. Pain 85:287-289

    • ↵18. Penn RD and Paice JA (2000) Adverse effects associated with the intrathecal administration of Ziconotide. Pain 85:291-296

    • ↵19. McGuire D, Bowersox S, Fellmann JD, and Luther RR (1997) Sympatholysis after neuron-specific, N-type, voltage-sensitive calcium channel blockade: first demonstration of N-channel function in humans. J Cardio Pharm 30:400-403

    • ↵20. Ramilo CA, Zafaralla GC, Nadasdi L, Hammerland LG, Yoshikami D, Gray WR, Kristipati R, Ramachandran J, Miljanich G, and Olivera BM (1992) Novel α- and ω-conotoxins from Conus striatus venom. Biochemistry 31:9919-9926

    • ↵21. Grantham CJ, Main MJ, and Cannell MB (1994) Fluspirilene block of N-type calcium current in NGF-differentiated PC12cells. Br J Pharmacol 111:483-488

    • ↵22. Sah DW and Bean BP (1994) Inhibition of P-type and N-type calcium channels by dopamine receptor antagonists. Mol Pharmacol 45:84-92

    • ↵23. Weinsberg F, Bickmeyer U, and Wiegand H (1994) Effects of tetrandrine on calcium channel currents of bovine chromaffin cells. Neuropharmacology 33:885-890

    • ↵24. Sutton KG, Siok C, Stea A, Zamponi GW, Heck SD, Volkmann RA, Ahlijanian MK, and Snutch TP (1998) Inhibition of neuronal calcium channels by a novel peptide spider toxin, DW13.3. Mol Pharmacol 54:407-418

    • ↵25. Roullet JB, Spaetgens RL, Burlingame T, Feng ZP, and Zamponi GW (1999) Modulation of neuronal voltage-gated calcium channels by farnesol. J Biol Chem 274:25439-25446

    • ↵26. Hu LY, Ryder TR, Rafferty MF, Siebers KM, Malone T, Chatterjee A, Feng MR, Lotarski SM, Rock DM, Stoehr SJ, et al. (2000) Neuronal N-type calcium channel blockers: a series of 4-piperidinylanilineanalogs with analgesic activity. Drug Des Discov 17:85-93

    • ↵27. Hu LY, Ryder TR, Rafferty MF, Taylor CP, Feng MR, Kuo BS, Lotarski SM, Miljanich GP, Millerman E, Siebers KM, et al. (2000) The discovery of [1-(4-dimethylaminobenzyl)-piperidin-4-yl]-[4-(3,3-dimethylbutyl)-phenyl]-(3-methyl-but-2-enyl)-amine, an N-type Ca2+ channel blocker with oral activity for analgesia. Bioorg Med Chem 8:1203-1212

    • ↵28. Ryder TR, Hu LY, Rafferty MF, Millerman E, Szoke BG, and Tarczy-Hornoch K (1999) Multiple parallel synthesis of N,N-dialkyldipeptidylamines as N-type calcium channel blockers. Bioorg Med Chem Lett 9:1813-1818

    • ↵29. Kamatchi GL, Chan CK, Snutch T, Durieux ME, and Lynch III C (1999) Volatile anesthetic inhibition of neuronal Ca channel currents expressed in Xenopus oocytes. Brain Res 831:85-96

    • ↵30a. Snutch TP and Zamponi GW (2000) inventors, NeuroMed Technologies, Inc., assignee. Calcium channel blockers. U.S. patent 6,011,035. 2000 Jan 4

    • ↵30b. Snutch TP and Zamponi GW (2001) inventors, NeuroMed Technologies, Inc., assignee. Calcium channel blockers. U.S. patent 6,294,533. 2001 Sep 25

    • ↵30c. Snutch TP (2001) inventor, NeuroMed Technologies, Inc., assignee. Fused ring calcium channel blockers. U.S. patent 6,310,059. 2001 Oct 30

    • ↵30d. Snutch TP (2002) inventor, NeuroMed Technologies, Inc., assignee. Preferentially substituted calcium channel blockers. U.S. patent 6,387,897. 2002 May 14

    • ↵30e. Snutch TP (2002) inventor, NeuroMed Technologies, Inc., assignee. Partially saturated calcium channel blockers. U.S. patent 6,492,375. 2002 Dec 10

    • ↵31. Beedle AM and Zamponi GW (2000) Block of voltage-dependent calcium channels by aliphatic monoamines. Biophys J 79:260-270

    • ↵32. Lewis RJ, Nielson KJ, Craik DJ, Loughnan ML, Adams DA, Sharpe IA, Luchian T, Adams DJ, Bond T, Thomas L, et al. (2000) Novel ω-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes. J Biol Chem 275:35335-35344

    • ↵33. Martin DJ, McClelland D, Herd MB, Sutton KG, Hall MD, Lee K, Pinnock RD, and Scott RH (2002) Gabapentin-mediated inhibition of voltage-activated Ca2+ channel currents in cultured sensory neurones is dependent on culture conditions and channel subunit expression. Neuropharmacology 42:353-366

    • ↵34. Sutton KG, Martin DJ, Pinnock RD, Lee K, and Scott RH (2002) Gabapentin inhibits high-threshold calcium channel currents in cultured rat dorsal root ganglion neurones. Br J Pharmacol 135:257-265

    • ↵35. Mori Y, Nishida M, Shimizu S, Ishii M, Yoshinaga T, Ino M, Sawada K, and Niidome T (2002) Ca2+ channel α1B subunit (Cav2.2) knockout mouse reveals a predominant role of N-type channels in the sympathetic regulation of the circulatory system. Trends Cardiovasc Med 12:270-275

    • ↵36. Beuckmann CT, Sinton CM, Miyamoto N, Ino M, and Yanagisawa M (2003) N-type calcium channel α1B subunit (CaV2.2) knock-out mice display hyperactivity and vigilance state differences. J Neurosci 23:6793-6797

    • ↵37. Ghasemzadeh MB, Pierce RC, and Kalivas PW (1999) The monoamine neurons of the rat brain preferentially express a splice variant of α1B subunit of the N-type calcium channel. J Neurochem 73:1718-1723

    • ↵38. Pan JQ and Lipscombe D (2000) Alternative splicing in the cytoplasmic II-III loop of the N-type Ca channel α1B subunit: functional differences are beta subunit-specific. J Neurosci 20:4769-4775

    • ↵39. Lin Y, McDonough SI, and Lipscombe D (2004) Alternative splicing in the voltage-sensitive region of N-type CaV2.2 channels modulates channel kinetics. J Neurophysiol 92:2820-2830

    • ↵40. Lin Z, Haus S, Edgerton J, and Lipscombe D (1997) Identification of functionally distinct isoforms of the N-type Ca2+ channel in rat sympathetic ganglia and brain. Neuron 18:153-166

    • ↵41. Lin Z, Lin Y, Schorge S, Pan JQ, Beierlein M, and Lipscombe D (1999) Alternative splicing of a short cassette exon in a1B generates functionally distinct N-type calcium channels in central and peripheral neurons. J Neurosci 19:5322-5331

    • ↵42. Bell TJ, Thaler C, Castiglioni AJ, Helton TD, and Lipscombe D (2004) Cell specific alternative splicing increases calcium current density in the pain pathway. Neuron 42:127-138

    • ↵43. Rettig J, Sheng ZH, Kim DK, Hodson CD, Snutch TP, and Catterall WA (1996) Isoform-specific interaction of the a1A subunits of brain Ca2+ channels with the presynaptic proteins syntaxin and SNAP-25. Proc Natl Acad Sci USA 93:7363-7368

    • ↵44. Maximov A, Sudhof TC, and Bezprozvanny I (1999) Association of neuronal calcium channels with modular adaptor proteins. J Biol Chem 274:24453-24456

    • ↵45. Kaneko S, Cooper CB, Nishioka N, Yamasaki H, Suzuki A, Jarvis SE, Akaike A, Satoh M, and Zamponi GW (2002) Identification and characterization of novel human CaV2.2 (alpha 1B) calcium channel variants lacking the synaptic protein interaction site. J Biol Chem 22:82-92

  • TABLE 8

    CaV2.3 channels

    Channel name CaV2.3
    Description Voltage-gated calcium channel α1 subunit
    Other names R-type, α1E; rbE-II (in rat)1; BII-1, BII-2 (in rabbit)2
    Molecular information Human: 2251aa, L29384, 2270aa, L29385,3 chr0.1q25-q31, CACNA1E
    Rat: 2222aa,1 GenBank accession no. L15453
    Mouse: 2272aa, Q61290
    Associated subunits α2δ/β, possibly γ
    Functional assays Voltage-clamp, patch-clamp, calcium imaging, neurotransmitter release
    Current ICa,R
    Conductance Not established
    Ion selectivity Ba2+ ∼ Ca2+ (rat)4; Ba2+ > Ca2+ (human)3
    Activation Va = +3.5 mV, τa = 1.3 ms at 0 mV (human α1E/α2δ/β1-3, 15 mM Ba2+ charge carrier in HEK293 cells)3
    Va = –29.1 mV, τa = 2.1 ms at –10 mV (rat α1E/α2δ/β1b, 4 mM Ba2+ charge carrier in Xenopus oocytes)1
    Inactivation Vh = –71 mV, τh = 74 ms at 0 mV (human α1E/α2δ/β1-3, 15 mM Ba2+ charge carrier in HEK293 cells)3; Vh = –78.1 mV, τh = 100 ms at –10 mV (rat α1E/α2δ/β1b, 4 mM Ba2+ charge carrier in Xenopus oocytes)1
    Activators None
    Gating modifiers None
    Blockers SNX-482, Ni2+ (IC50 = 27 μM), Cd2+ (IC50 = 0.8 μM), mibefradil (IC50 = 0.4 μM),10 volatile anesthetics11
    Radioligands None
    Channel distribution Neurons (cell bodies, dendrites, some presynaptic terminals), heart, testes, pituitary
    Physiological functions Neurotransmitter release, repetitive firing, long-term potentiation, post-tetanic potentiation, neurosecretion12,13,14
    Mutations and pathophysiology No point mutations in the native Cav2.3 gene have been reported; mice deficient for the Cav2.3 gene retain a substantial cerebellar R-type current,5 suggesting that R-type currents actually reflect a heterogeneous mixture of channels; homozygous Cav2.3-null mice survive to adulthood, reproduce, and are apparently behaviorally normal5,6; mutant mice exhibit an increased resistance to formalin-induced pain, suggesting an involvement of the Cav2.3 calcium channel in transmitting and/or the development of somatic inflammatory pain6
    Pharmacological significance See “Comments”
    Comments Cav2.3 has been variously reported to encode a novel type of calcium channel with properties shared between both low- and high-threshold calcium channels1,4 or a type of high-threshold channel resistant to DHPs, ω-agatoxin-IVA, and ω-conotoxin-GVIA and called R-type (for “residual”)7
    The tarantula toxin SNX-482 blocks exogenously expressed Cav2.3 currents8 but is only partially effective on native cerebellar R-type currents,9 suggesting that Cav2.3 does not always conduct a significant portion of the R-type current as originally defined7; identified regions of alternative splicing include the domain II-III linker and carboxyl terminus and have been shown to affect channel kinetics and Ca2+-dependent stimulation1,2,3,15,16

    • aa, amino acids; chr., chromosome; HEK, human embryonic kidney; DHP, dihydropyridine.

    • ↵1. Soong TW, Stea A, Hodson CD, Dubel SJ, Vincent SR, and Snutch TP (1993) Structure and functional expression of a member of the low voltage-activated calcium channel family. Science 260:1133-1136

    • ↵2. Niidome T, Kim MS, Friedrich T, and Mori Y (1992) Molecular cloning and characterization of a novel calcium channel from rabbit brain. FEBS Lett 308:7-13

    • ↵3. Williams ME, Marubio LM, Deal CR, Hans M, Brust PF, Philipson LH, Miller RJ, Johnson EC, Harpold MM, and Ellis SB (1994) Structure and functional characterization of neuronal α1E calcium channel subtypes. J Biol Chem 269:22347-22357

    • ↵4. Bourinet E, Zamponi GW, Stea A, Soong TW, Lewis BA, Jones LP, Yue DT, and Snutch TP(1996) The α1E calcium channel exhibits permeation properties similar to low-voltage-activated calcium channels. J Neurosci, 16:4983-4993

    • ↵5. Wilson SM, Toth PT, Oh SB, Gillard SE, Volsen S, Ren D, Philipson LH, Lee EC, Fletcher CF, Tessarollo L, et al. (2000) The status of voltage dependent calcium channels in α1E knockout mice. J Neurosci 20:8566-8571

    • ↵6. Saegusa H, Kurhara T, Zong S, Minowa O, Kazuno A, Han W, Matsuda Y, Yamanaka H, Osanai M, Noda T, et al. (2000) Altered pain responses in mice lacking α1E subunit of the voltage dependent Ca channel. Proc Natl Acad Sci USA 97:6132-6137

    • ↵7. Randall A and Tsien RW (1995) Pharmacological dissection of multiple types of calcium channel currents in rat cerebellar granule neurons. J Neurosci 15:2995-3012

    • ↵8. Newcombe R, Szoke B, Palma A, Wang G, Chen XH, Hopkins W, Cong R, Miller J, Urge L, Tarczy-Hornoch K, et al. (1998) Selective peptide antagonist of the class E calcium channel from the venom of the tarantula Hysterocrates gigas. Biochemistry 37:15353-15362

    • ↵9. Tottene A, Volsen S, and Pietrobon D (2000) α1E subunits form the pore of three cerebellar R-type calcium channels with different pharmacological and permeation properties. J Neurosci 20:171-178

    • ↵10. Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP, and Nargeot J (2000) Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels. Neuropharmacology 39:1-10

    • ↵11. Kamatchi GL, Chan CK, Snutch T, Durieux ME, and Lynch III C (1999) Volatile anesthetic inhibition of neuronal Ca channel currents expressed in Xenopus oocytes. Brain Res 831:85-96

    • ↵12. Dietrich D, Kirschstein T, Kukley M, Pereverzev A, von der Brelie C, Schneider T, and Beck H (2003) Functional specialization of presynaptic Cav2.3 Ca2+ channels. Neuron 39:483-496

    • ↵13. Jing X, Li DQ, Olofsson CS, Salehi A, Surve VV, Caballero J, Ivarsson R, Lundquist I, Pereverzev A, Schneider T, et al. (2005) CaV2.3 calcium channels control second-phase insulin release. J Clin Investig 115:146-154

    • ↵14. Pereverzev A, Salehi A, Mikhna M, Renstrom E, Hescheler J, Weiergraber M, Smyth N, and Schneider T (2005) The ablation of the Cav2.3/E-type voltage-gated Ca2+ channel causes a mild phenotype despite an altered glucose induced glucagon response in isolated islets of Langerhans. Eur J Pharmacol 511:65-72

    • ↵15. Pereverzev A, Leroy J, Krieger A, Malecot CO, Hescheler J, Pfitzer G, Klockner U, and Schneider T (2002) Alternate splicing in the cytosolic II-III loop and the carboxy terminus of human E-type voltage-gated Ca2+ channels: electrophysiological characterization of isoforms. Mol Cell Neurosci 21:352-365

    • ↵16. Klocker U, Pereverzev A, Leroy J, Krieger A, Vajna R, Pfitzer G, Hescheler J, Malecot CO, and Schneider T (2004) The cytoplasmic loop of Cav2.3 provides an essential determinant for the phorbol ester-mediated stimulation of E-type Ca2+ channel activity. Eur J Neurosci 19:2659-2668

  • TABLE 9

    CaV3.1 channels

    Channel name Cav3.1
    Description Voltage-gated calcium channel α1 subunit
    Other names T-type, α13.1, α1G
    Molecular information Human: 2377aa, O43497, NM_018896, chr. 17q22, CACNA1G1
    Rat: 2254aa, O54898, AF027984
    Mouse: 2288aa, CAI25956, NM_009783 (see “Comments”)
    Associated subunits No biochemical evidence, small changes induced by α2δ12 and α2δ23,4
    Functional assays Voltage-clamp, calcium imaging
    Current ICa,T
    Conductance 7.5pS1
    Ion selectivity Sr2+ > Ba2+ = Ca2+
    Activation Va = —46 mV, τa = 1 ms at —10 mV5,6
    Inactivation Vh = —73 mV, τh = 11 ms at —10 mV5,6
    Activators Not established
    Gating modifiers Kurtoxin, IC50 = 15 nM7
    Blockers No subtype-specific blocker8; selective for Cav3.x relative to Cav1.x and Cav2.x: mibefradil,9,10 U92032,11 penfluridol and pimozide12; nonselective: nickel (IC50 = 250 μM),13 amiloride14
    Radioligands None
    Channel distribution Brain, especially soma and dendrites of neurons in olfactory bulb, amygdala, cerebral cortex, hippocampus, thalamus, hypothalamus, cerebellum, brain stem (human RNA blots,1,5 rat in situ hybridization15 and immunocytochemistry16); ovary, placenta, heart (especially sinoatrial node; mouse in situ hybridization17)
    Physiological functions Thalamic oscillations18
    Mutations and pathophysiology Not established
    Pharmacological significance May mediate effect of absence antiepileptic drugs such as ethosuximide19 and other thalamocortical dysrhythmias20
    Comments Splice variants that differ in their voltage dependence have been cloned5

    • aa, amino acids; chr., chromosome; U92032, 7-[[4-bis(fluorophenyl)methyl]-1-piperazinyl]methyl-2-[(2-hydroxyethyl)a mino]4-(1-methylethyl)-2,4,6-cycloheptatrien-1-one.

    • ↵1. Perez-Reyes E, Cribbs LL, Daud A, Lacerda AE, Barclay J, Williamson MP, Fox M, Rees M, and Lee J-H (1998) Molecular characterization of a neuronal low voltage-activated T-type calcium channel. Nature (Lond) 391:896-900

    • ↵2. Dolphin AC, Wyatt CN, Richards J, Beattie RE, Craig P, Lee J-H, Cribbs LL, Volsen SG, and Perez-Reyes E (1999) The effect of α2δ and other accessory subunits on expression and properties of the calcium channel α1G. J Physiol (Lond) 519.1:35-45

    • ↵3. Gao B, Sekido Y, Maximov A, Saad M, Forgacs E, Latif F, Lerman M, Lee J-H, Perez-Reyes E, Bezprozvanny I, et al. (2000) Functional properties of a new voltage-dependent calcium channel α2δ auxiliary subunit gene (CACNA2D2). J Biol Chem 275:12237-12242

    • ↵4. Hobom M, Dai S, Marais E, Lacinova L, Hofmann F and Klugbauer N (2000) Neuronal distribution and functional characterization of the calcium channel α2δ2 subunit. Eur J Neurosci 12:1217-1226

    • ↵5. Monteil A, Chemin J, Bourinet E, Mennessier G, Lory P, and Nargeot J (2000) Molecular and functional properties of the human α1G subunit that forms T-type calcium channels. J Biol Chem 275:6090-6100

    • ↵6. Klöckner U, Lee JH, Cribbs LL, Daud A, Hescheler J, Pereverzev A, Perez-Reyes E, and Schneider T (1999) Comparison of the Ca2+ currents induced by expression of three cloned α1 subunits, α1G, α1H and α1I, of low-voltage-activated T-type Ca2+ channels. Eur J Neurosci 11:4171-4178

    • ↵7. Chuang RS, Jaffe H, Cribbs L, Perez-Reyes E, and Swartz KJ (1998) Inhibition of T-type voltage-gated calcium channels by a new scorpion toxin. Nat Neurosci 1:668-674

    • ↵8. Heady TN, Gomora JC, Macdonald TL, and Perez-Reyes E (2001) Molecular pharmacology of T-type Ca2+ channels. Jpn J Pharmacol 85:339-350

    • ↵9. Perchenet L, Bénardeau A, and Ertel EA (2000) Pharmacological properties of Cav3.2, a low voltage-activated Ca2 + channel cloned from human heart. Naunyn Schmiedeberg's Arch Pharmacol 361:590-599

    • ↵10. Martin RL, Lee JH, Cribbs LL, Perez-Reyes E, and Hanck DA (2000) Mibefradil block of cloned T-type calcium channels. J Pharmacol Exp Ther 295:302-308

    • ↵11. Avery RB and Johnston D (1997) Ca2+ channel antagonist U-92032 inhibits both T-type Ca2+ channels and Na+ channels in hippocampal CA1 pyramidal neurons. J Neurophysiol 77:1023-1028

    • ↵12. Santi CM, Cayabyab FS, Sutton KG, McRory JE, Mezeyova J, Hamming KS, Parker D, Stea A, and Snutch TP (2002) Differential inhibition of T-type calcium channels by neuroleptics. J Neurosci 22:396-403

    • ↵13. Lee JH, Gomora JC, Cribbs LL, and Perez-Reyes E (1999) Nickel block of three cloned T-type calcium channels: low concentrations selectively block α1H. Biophys J 77:3034-3042

    • ↵14. Lacinova L, Klugbauer N, and Hofmann F (2000) Regulation of the calcium channel α1G subunit by divalent cations and organic blockers. Neuropharmacology 39:1254-1266

    • ↵15. Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, and Bayliss DA (1999) Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci 19:1895-1911

    • ↵16. Craig PJ, Beattie RE, Folly EA, Banerjee MD, Reeves MB, Priestley JV, Carney SL, Sher E, Perez-Reyes E, and Volsen SG (1999) Distribution of the voltage-dependent calcium channel α1G subunit mRNA and protein throughout the mature rat brain. Eur J Neurosci 11:2949-2964

    • ↵17. Bohn G, Moosmang S, Conrad H, Ludwig A, Hofmann F, and Klugbauer N (2000) Expression of T- and L-type calcium channel mRNA in murine sinoatrial node. FEBS Lett 481:73-76

    • ↵18. Perez-Reyes E (2003) Molecular physiology of low-voltage-activated T-type calcium channels. Physiol Rev 83:117-161

    • ↵19. Gomora JC, Daud AN, Weiergräber M, and Perez-Reyes E (2001) Block of cloned human T-type calcium channels by succinimide antiepileptic drugs. Mol Pharmacol 60:1121-1132

    • ↵20. Llinás RR, Ribary U, Jeanmonod D, Kronberg E, and Mitra PP (1999) Thalamocortical dysrhythmia: a neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc Natl Acad Sci USA 96:15222-15227

  • TABLE 10

    CaV3.2 channels

    Channel name Cav3.2
    Description Voltage-gated calcium channel α1 subunit
    Other names T-type, α13.2, α1H
    Molecular information Human: 2353aa, O95180, AF051946, chr0.16p13.3, CACNA1H1
    Rat: 2359aa, AAG35187, AF290213
    Mouse: 2365aa, NP_067390, NM_021415
    Associated subunits Not established
    Functional assays Voltage-clamp, calcium imaging
    Current ICa,T
    Conductance 9pS2
    Ion selectivity Ba2+ = Ca2+
    Activation Va = –46 mV, τa = 2 ms at –10 mV3
    Inactivation Vh = –72 mV, τh = 16 ms at –10 mV3
    Activators None
    Gating modifiers Kurtoxin4
    Blockers Cav3.2 is more sensitive than Cav3.1 to block by nickel (IC50 = 12 μM)5 and possibly phenytoin6 and amiloride2,7; selective for Cav3.x relative to Cav1.x and Cav2.x: mibefradil,8,9 U92032,10 penfluridol and pimozide,11 and amiloride12; nonselective: nimodipine,2 anesthetics5
    Radioligands None
    Channel distribution Kidney (human Northern1), rat smooth muscle (RT-PCR13), liver (human Northern1), adrenal cortex (rat, bovine; in situ hybridization and RT-PCR14), brain (especially in olfactory bulb, striatum, cerebral cortex, hippocampus, reticular thalamic nucleus; rat in situ hybridization15), and heart (especially sinoatrial node; mouse in situ hybridization16)
    Physiological functions Smooth muscle contraction,17 smooth muscle proliferation,18 aldosterone secretion,19 cortisol secretion20
    Mutations and pathophysiology Single nucleotide polymorphisms associated with childhood absence epilepsy patients in a Chinese population21
    Pharmacological significance May mediate effect of absence antiepileptic drugs such as ethosuximide22 and other thalamocortical dysrhythmias23; potential drug target in hypertension and angina pectoris24
    Comments Splice variation found in the linker connecting repeat 3 and 425

    • aa, amino acids; chr., chromosome; RT-PCR, reverse-transcriptase-polymerase chain reaction.

    • ↵1. Cribbs LL, Lee JH, Yang J, Satin J, Zhang Y, Daud A, Barclay J, Williamson MP, Fox M, Rees M, et al. (1998) Cloning and characterization of α1H from human heart, a member of the T-type Ca2+ channel gene family. Circ Res 83:103-109

    • ↵2. Williams ME, Washburn MS, Hans M, Urrutia A, Brust PF, Prodanovich P, Harpold MM, and Stauderman KA (1999) Structure and functional characterization of a novel human low-voltage activated calcium channel. J Neurochem 72:791-799

    • ↵3. Klöckner U, Lee JH, Cribbs LL, Daud A, Hescheler J, Pereverzev A, Perez-Reyes E, and Schneider T (1999) Comparison of the Ca2+ currents induced by expression of three cloned α1 subunits, α1G, α1H and α1I, of low-voltage-activated T-type Ca2+ channels. Eur J Neurosci 11:4171-4178

    • ↵4. Chuang RS, Jaffe H, Cribbs L, Perez-Reyes E, and Swartz KJ (1998) Inhibition of T-type voltage-gated calcium channels by a new scorpion toxin. Nat Neurosci 1:668-674

    • ↵5. Lee JH, Gomora JC, Cribbs LL, and Perez-Reyes E (1999) Nickel block of three cloned T-type calcium channels: low concentrations selectively block α1H. Biophys J 77:3034-3042

    • ↵6. Todorovic SM, Perez-Reyes E, and Lingle CJ (2000) Anticonvulsants but not general anesthetics have differential blocking effects on different T-type current variants. Mol Pharmacol 58:98-108

    • ↵7. Lacinova L, Klugbauer N, and Hofmann F (2000) Regulation of the calcium channel α1G subunit by divalent cations and organic blockers. Neuropharmacology 39:1254-1266

    • ↵8. Perchenet L, Bénardeau A, and Ertel EA (2000) Pharmacological properties of CaV3.2, a low voltage-activated Ca2+ channel cloned from human heart. Naunyn Schmiedeberg's Arch Pharmacol 361:590-599

    • ↵9. Martin RL, Lee JH, Cribbs LL, Perez-Reyes E, and Hanck DA (2000) Mibefradil block of cloned T-type calcium channels. J Pharmacol Exp Ther 295:302-308

    • ↵10. Avery RB and Johnston D (1997) Ca2+ channel antagonist U-92032 inhibits both T-type Ca2+ channels and Na+ channels in hippocampal CA1 pyramidal neurons. J Neurophysiol 77:1023-1028

    • ↵11. Santi CM, Cayabyab FS, Sutton KG, McRory JE, Mezeyova J, Hamming KS, Parker D, Stea A, and Snutch TP (2002) Differential inhibition of T-type calcium channels by neuroleptics. J Neurosci 22:396-403

    • ↵12. Tang C-M, Presser F, and Morad M (1988) Amiloride selectively blocks the low threshold (T) calcium channel. Science 240:213-215

    • ↵13. Hansen PB, Jensen BL, Andreasen D, and Skøtt O (2001) Differential expression of T- and L-type voltage-dependent calcium channels in renal resistance vessels. Circ Res 89:630-638

    • ↵14. Schrier AD, Wang H, Talley EM, Perez-Reyes E, and Barrett PQ (2001) α1H T-type Ca2+ channel is the predominant subtype expressed in bovine and rat zona glomerulosa. Am J Physiol Cell Physiol 280:C265-C272

    • ↵15. Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, and Bayliss DA (1999) Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci 19:1895-1911

    • ↵16. Bohn G, Moosmang S, Conrad H, Ludwig A, Hofmann F, and Klugbauer N (2000) Expression of T- and L-type calcium channel mRNA in murine sinoatrial node. FEBS Lett 481:73-76

    • ↵17. Sarsero D, Fujiwara T, Molenaar P, and Angus JA (1998) Human vascular to cardiac tissue selectivity of L- and T-type calcium channel antagonists. Br J Pharmacol 125:109-119

    • ↵18. Schmitt R, Clozel JP, Iberg N, and Bühler FR (1995) Mibefradil prevents neointima formation after vascular injury in rats. Possible role of the blockade of the T-type voltage-operated calcium channel. Arterioscler Thromb Vasc Biol 15:1161-1165

    • ↵19. Rossier MF, Ertel EA, Vallotton MB, and Capponi AM (1998) Inhibitory action of mibefradil on calcium signaling and aldosterone synthesis in bovine adrenal glomerulosa cells. J Pharmacol Exp Ther 287:824-831

    • ↵20. Gomora JC, Xu L, Enyeart JA, and Enyeart JJ (2000) Effect of mibefradil on voltage-dependent gating and kinetics of T-type Ca2+ channels in cortisol-secreting cells. J Pharmacol Exp Ther 292:96-103

    • ↵21. Chen YC, Lu JJ, Pan H, Zhang YH, Wu HS, Xu KM, Liu XY, Jiang YW, Bao XH, Yao ZJ, et al. (2003) Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol 54:239-243

    • ↵22. Gomora JC, Daud AN, Weiergräber M, and Perez-Reyes E (2001) Block of cloned human T-type calcium channels by succinimide antiepileptic drugs. Mol Pharmacol 60:1121-1132

    • ↵23. Llinás R, Ribary U, Jeanmonod D, Kronberg E, and Mitra PP (1999) Thalamocortical dysrhythmia: a neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc Natl Acad Sci USA 96:15222-15227

    • ↵24. Ertel SI, Ertel EA, and Clozel JP (1997) T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. Cardiovasc Drugs Ther 11:723-739

    • ↵25. Jagannathan S, Punt EL, Gu Y, Arnoult C, Sakkas D, Barratt CLR, and Publicover SJ (2002) Identification and localization of T-type voltage-operated calcium channel subunits in human male germ cells. Expression of multiple isoforms. J Biol Chem 277:8449-8456

  • TABLE 11

    CaV3.3 channels

    Channel name Cav3.3
    Description Voltage-gated calcium channel α1 subunit
    Other names T-type, α13.3, α1I
    Molecular information Human: 2251aa, AAM67414, AF393329, chr. 22q13.1, CACNA1I1
    Rat: 1835aa, AF086827, AAD17796
    Mouse 2753aa: XP_139476, XM_139476
    Associated subunits No biochemical evidence, small changes induced by γ22
    Functional assays Voltage-clamp, calcium imaging
    Current ICa,T
    Conductance 11pS1
    Ion selectivity Ba2+ = Ca2+
    Activation Va = –44 mV, τa = 7 ms at –10 mV4
    Inactivation Vh = –72 mV, τh = 69 ms at –10 mV4
    Activators Not established
    Gating modifiers None
    Blockers No subtype-specific blocker5; selective for Cav3.x relative to Cav1.x and Cav2.x: mibefradil,6,7 U92032,8 penfluridol,9 pimozide9; nonselective: nickel (IC50 = 216 μM)10
    Radioligands None
    Channel distribution Brain, especially olfactory bulb, striatum, cerebral cortex, hippocampus, reticular nucleus, lateral habenula, cerebellum (rat in situ hybridization,11 human Northern12
    Physiological functions Thalamic oscillations13
    Mutations and pathophysiology Not established
    Pharmacological significance May mediate effect of absence antiepileptic drugs such as ethosuximide14 and other thalamocortical dysrhythmias15
    Comments Splice variants have been reported16

    • aa, amino acids; chr., chromosome.

    • ↵1. Lee JH, Daud AN, Cribbs LL, Lacerda AE, Pereverzev A, Klöckner U, Schneider T, and Perez-Reyes E (1999) Cloning and expression of a novel member of the low voltage-activated T-type calcium channel family. J Neurosci 19:1912-1921

    • ↵2. Green PJ, Warre R, Hayes PD, McNaughton NC, Medhurst AD, Pangalos M, Duckworth DM, and Randall AD (2001) Kinetic modification of the α1I subunit-mediated T-type Ca2+ channel by a human neuronal Ca2+ channel γ subunit. J Physiol (Lond) 533:467-478

    • ↵3. McRory JE, Santi CM, Hamming KS, Mezeyova J, Sutton KG, Baillie DL, Stea A, and Snutch TP (2001) Molecular and functional characterization of a family of rat brain T-type calcium channels. J Biol Chem 276:3999-4011

    • ↵4. Klöckner U, Lee JH, Cribbs LL, Daud A, Hescheler J, Pereverzev A, Perez-Reyes E, and Schneider T (1999) Comparison of the Ca2+ currents induced by expression of three cloned α1 subunits, α1G, α1H and α1I, of low-voltage-activated T-type Ca2+ channels. Eur J Neurosci 11:4171-4178

    • ↵5. Heady TN, Gomora JC, Macdonald TL, and Perez-Reyes E (2001) Molecular pharmacology of T-type Ca2+ channels. Jpn J Pharmacol 85:339-350

    • ↵6. Perchenet L, Bénardeau A, and Ertel E.(2000) Pharmacological properties of Cav3.2, a low voltage-activated Ca2+ channel cloned from human heart. Naunyn Schmiedeberg's Arch Pharmacol 361:590-599

    • ↵7. Martin RL, Lee JH, Cribbs LL, Perez-Reyes E, and Hanck DA (2000) Mibefradil block of cloned T-type calcium channels. J Pharmacol Exp Ther 295:302-308

    • ↵8. Avery RB and Johnston D (1997) Ca2+ channel antagonist U-92032 inhibits both T-type Ca2+ channels and Na+ channels in hippocampal CA1 pyramidal neurons. J Neurophysiol 77:1023-1028

    • ↵9. Santi CM, Cayabyab FS, Sutton KG, McRory JE, Mezeyova J, Hamming KS, Parker D, Stea A, and Snutch TP (2002) Differential inhibition of T-type calcium channels by neuroleptics. J Neurosci 22:396-403

    • ↵10. Lee JH, Gomora JC, Cribbs LL, and Perez-ReyesE (1999) Nickel block of three cloned T-type calcium channels: low concentrations selectively block α1H. Biophys J 77:3034-3042

    • ↵11. Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, and Bayliss DA (1999) Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci 19:1895-1911

    • ↵12. Monteil A, Chemin J, Leuranguer V, Altier C, Mennessier G, Bourinet E, Lory P, and Nargeot J (2000) Specific properties of T-type calcium channels generated by the human α1I subunit. J Biol Chem 275:16530-16535

    • ↵13. Perez-Reyes E (2003) Molecular physiology of low-voltage-activated T-type calcium channels. Physiol Rev 83:117-161

    • ↵14. Gomora JC, Daud AN, Weiergräber M, and Perez-Reyes E (2001) Block of cloned human T-type calcium channels by succinimide antiepileptic drugs. Mol Pharmacol 60:1121-1132

    • ↵15. Llinás RR, Ribary U, Jeanmonod D, Kronberg E, and Mitra PP (1999) Thalamocortical dysrhythmia: a neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc Natl Acad Sci USA 96:15222-15227

    • ↵16. Mittman S, Guo J, Emerick MC, and Agnew WS (1999) Structure and alternative splicing of the gene encoding α1I, a human brain T calcium channel α1 subunit. Neurosci Lett 269:121-124

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OtherIUPHAR Compendium of Voltage-Gated Ion Channels 2005

International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels

William A. Catterall, Edward Perez-Reyes, Terrance P. Snutch and Joerg Striessnig
Pharmacological Reviews December 1, 2005, 57 (4) 411-425; DOI: https://doi.org/10.1124/pr.57.4.5
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