Q J Med 1999; 92: 133-141
© 1999 Association of Physicians
Mini-review |
Calcium channelopathies
From the Department of Medicine (Neurology), Groote Schuur Hospital, Cape Town, South Africa
Dr M.G. Benatar, Beth Israel Deaconess Medical Center—East, 330 Brookline Avenue, Medicine, GZ-207, Boston, Massachusetts 02115, USA. e-mail: mbenatar{at}caregroup.harvard.edu
Introduction
Calcium (Ca2+) is an essential signalling molecule in many biological systems, and normal intracellular calcium levels at ~100 nM are 20 000-fold lower than the 2 mM concentration found extracellularly. Homoeostatic mechanisms are tightly controlled to enable Ca2+ to mediate a variety of cellular functions and to prevent sustained rises in intracellular calcium concentration which result in cell death.
Abnormalities of calcium homoeostasis are recognized to play an important role in the excitotoxic damage which occurs in the setting of cerebrovascular disease and various neurodegenerative diseases.1 More recently, however, abnormalities of the voltage-gated calcium channel (VGCC), one of the key regulators of intracellular calcium concentration, have been implicated in a wide range of human diseases, including migraine,2 episodic ataxia,2 spinocerebellar degeneration,3 the Lambert-Eaton myasthenic syndrome,4 hypokalaemic periodic paralysis5 and X-linked congenital stationary night blindness (xlCSNB).6,7 It has been suggested that amyotrophic lateral sclerosis may be mediated by antibodies directed against the VGCC,8 but the weight of evidence does not support this hypothesis.9 Of further interest is the implication of the voltage-gated calcium channel in spontaneous mouse models of epilepsy10–12 and the muscular dysgenesis mouse.13
Recently there have been many advances in the understanding of the molecular biology of the VGCC, and of the immunological and genetic basis for the disorders mentioned above, but our understanding of how such a diverse array of diseases may result from dysfunction of a single ion channel remains incomplete. In this article, I hope to summarize what is known about the VGCC with reference to these diseases and to speculate on the implications for other human diseases.
VGCC structure and function
VGCCs are transmembrane proteins that open in response to membrane depolarization and allow Ca2+ ions to enter the cell from the extracellular space. VGCCs are hetero-oligomeric proteins, comprising an 
1 subunit which forms the channel pore and voltage sensor as well as accessory ß, 
and 2
subunits. Until recently it was thought that an accessory -subunit was only present in skeletal muscle, but the existence of a neuronal -subunit, which associates with the 1B-subunit to form an N-type VGCC, is now recognized.14 These accessory subunits influence the voltage-dependence and kinetics of the 1 subunit. The 1 subunit comprises four domains (I–IV), each of which has six transmembrane-spanning helices (S1–S6). The fourth helix (S4) of each domain is highly charged and acts as a voltage sensor. The extracellular loop between the fifth (S5) and sixth (S6) helices dips into the membrane, and contributes to the channel pore (Figure 2
). The whole structure is envisaged to fold around, with the amino and carboxy termini meeting, to form a barrel-like structure.15,16 The ß-subunits lack -helices capable of spanning the membrane, suggesting that they are entirely intracellular in location. The 2 and subunits are encoded by a single gene and then processed to form two disulphide-linked polypeptides. The -subunit traverses the plasma membrane whilst the 2 component is entirely extracellular.17 The -subunit has four transmembrane domains (Figure 1).
|
|
VGCCs have been characterized genetically and pharmacologically (functionally), but these two approaches do not easily converge to yield a single coherent classification. Nine
1 (Table 1), one 2, one and four ß genes have been identified and cloned. Different accessory subunits combine with the various 1 subunits to form functionally distinct channels. Further channel diversity is generated by alternative splicing.
|
Dihydropyridine-sensitive L-type VGCCs are a group of high-voltage-activated calcium channels in which the pore-forming subunit may comprise the
1C, 1D, 1F or 1S subunit. Depolarization of the skeletal muscle membrane is sensed by the 1S-containing L-type VGCC which, through a physical interaction with the ryanodine receptor (via the LII–III intracellular loop), leads to a release of Ca2+ from the sarcoplasmic reticulum (SR). Movement of Ca2+ from the SR to the cytosol leads to muscle contraction. In contrast, Ca2+ entry via the P/Q-type VGCC controls neurotransmitter release at most central synapses and at the neuromuscular junction (NMJ). N-type VGCCs may also play a role in exocytosis at certain central synapses (Table 1
).18 The Lambert-Eaton myasthenic syndrome (LEMS)
LEMS is a disorder characterized by skeletal muscle weakness and autonomic dysfunction. In 60% of cases it is considered paraneoplastic and associated with an underlying small-cell lung carcinoma. Most evidence suggests that P/Q-type channels control acetylcholine release from motor nerve terminals at the NMJ19 and antibodies directed against P/Q-type VGCCs have been identified in the majority of patients with LEMS.20,21 Some patients with LEMS may also have antibodies directed against N- or L-type VGCCs or against the intracellular ß-subunit.22 The functional significance of these antibodies has been established by the demonstration of distorted active zones (comprising VGCCs and other proteins) in mice passively transferred with LEMS IgG23 and the ability of LEMS antisera to passively transfer the disease to animals.4 These anti-VGCC antibodies are thought to exert their effect by causing VGCC internalization and consequent reduction in the number of VGCCs available for coupling to neurotransmitter release. The specificity of these antibodies in reducing P/Q-type calcium currents has recently been demonstrated.24 These same antibodies have recently been shown to be responsible for the autonomic disturbance which also characterizes the LEMS.25
The muscular dysgenesis mouse, hypokalaemic periodic paralysis and malignant hyperthermia
The mouse autosomal recessive muscular dysgenesis (mdg) mutation results in paralysis. This disorder results from a single nucleotide deletion in the gene encoding the 1S skeletal muscle L-type VGCC. The consequence is a truncated protein with reduced levels of expression and defective excitation-contraction coupling13 (Table 2).
|
Hypokalaemic periodic paralysis is an autosomal dominant skeletal muscle disorder characterized by episodic weakness associated with low serum potassium. A variety of mutations, leading to amino-acid substitutions in the voltage-sensor (S4) segments, have been identified in the human skeletal muscle
1S gene (CACNA1S) on chromosome 1q31 in pedigrees with this disorder5 (Table 2). These mutations lead to enhanced Ca2+ channel inactivation and an abnormal resting membrane potential, but it is not clear how this altered function produces the clinical phenotype.
Malignant hyperthermia is an autosomal dominant disorder of skeletal muscle in which crises of hyperthermia, skeletal muscle rigidity, tachyarrythmia and acidosis may be triggered by volatile anaesthetics and depolarising muscle relaxants. Whilst in most cases it is caused by mutations in the ryanodine receptor (muscle sarcoplasmic reticular efflux Ca2+ channel),26 it has also been described in association with mutations in the 1S skeletal muscle L-type VGCC on chromosome 1q31,27 and linkage has been established to 7q21-22 which encompasses the CACNA2 gene for the 2 accessory subunit28 (Table 2). The 1S mutations are in the LII–III domain of the VGCC which are involved in the interaction with the ryanodine receptor.
Familial hemiplegic migraine, episodic ataxia-2 and spinocerebellar ataxia-6
The gene encoding the human P/Q-type VGCC 1A subunit has been identified on the long arm of chromosome 19 and designated CACNA1A.29 Three apparently distinct neurological disorders have been shown to be associated with different mutations in this gene (Table 2).
Familial hemiplegic migraine (FHM) is a rare autosomal dominant condition characterized by migraine with aura, ictal hemiparesis and, in some families, progressive cerebellar atrophy. Approximately 50% of patients with FHM show linkage to chromosome 19p, and four different missense mutations have been identified in these pedigrees in conserved functional domains of the channel.2 Moreover, this locus has been implicated in some patients with the more common forms of migraine with and without aura.30
Episodic ataxia type-2 (EA-2) is also an autosomal disorder and is characterized by paroxysmal attacks of cerebellar ataxia, vertigo, visual disturbance and dysarthria lasting from minutes to days, interictal nystagmus and cerebellar atrophy. Patients with EA-2 may show a dramatic response to acetazolamide, and it is speculated that this carbonic anhydrase inhibitor exerts its effect by altering neuronal pH. Two frame-shift mutations which result in premature stop-codons have been identified CACNA1A in four families with EA-2.2
The hereditary spinocerebellar ataxias are a genetically and neurologically heterogeneous group of conditions characterized by dysfunction of the cerebellum and its afferent and efferent connections. Spinocerebellar ataxia type-6 (SCA6) has been shown to be caused by a modest expansion of a polymorphic CAG repeat in the CACNA1A gene. This is translated into a polyglutamine repeat which is located within the C-terminal intracytoplasmic tail of the P/Q-type VGCC.3
X-linked congenital stationary night blindness
X-linked congenital stationary night blindness (xlCSNB) is a recessive non-progressive retinal disorder characterized by night blindness, decreased visual acuity, myopia, nystagmus and strabismus. This is a clinically and genetically heterogeneous condition with at least two different loci identified. The disorder is thought to result from impaired synaptic transmission between photoreceptors and second-order (bipolar) retinal neurons. A connection with calcium channels was first considered when it was established that L-type VGCCs were important in the release of glutamate from photoreceptor presynaptic terminals in the frog retina.31 More recently, a novel retinal-specific gene has been mapped to Xp11.23 and characterized as an L-type VGCC 1-subunit (which has been designated CACNA1F). Analysis of a number of different pedigrees with xlCSNB has demonstrated 15 different mutations which manifest as missense, nonsense, deletions or frameshifts with or without a premature stop codon.6,7 These mutations are summarized in Figure 2and Table 2. It is predicted that these represent loss-of-function mutations which would impair the influx of calcium required for the tonic release of glutamate from photoreceptor presynaptic terminals in darkness.6
Amyotrophic lateral sclerosis
It has been suggested that anti-VGCC antibodies may be present in a large proportion of patients with ALS.8 Other investigators, however, have been unable to confirm these results.32 Furthermore, the data which favour a pathogenic role of these antibodies in ALS include a number of apparent contradictions. Although it was initially shown that these antibodies enhance spontaneous neurotransmitter release from motor nerve terminals,33 this being taken to imply an activation of calcium channels, subsequent data have demonstrated an inhibitory effect on calcium channel currents.34 Moreover, any effect on the VGCC involved in neurotransmitter release at the NMJ implicates the P/Q-type VGCC, but (rabbit) skeletal muscle L-type VGCC were used in the seminal study claiming the presence of anti-VGCC antibodies in patients with ALS.8 There is no ready explanation for how antibodies directed against a skeletal muscle isoform of the VGCC may mediate a functional effect on the motor nerve.
The Tottering, Leaner, Lethargic andStargazer mice
The epilepsies are a heterogeneous group of paroxysmal disorders characterized by recurrent synchronized neuronal discharges. Many human epilepsy syndromes are likely to have an important genetic component, but efforts to identify these genetic factors are complicated by clinical and genetic heterogeneity. In the mouse, a number of single gene mutations that cause epilepsy have been identified and it is possible that investigation of these genes will provide insights into the human epilepsies.
The tottering mouse represents a recessive model of absence epilepsy characterized by ethosuxamide-responsive behavioural arrest accompanied by a generalized spike and wave discharge. In addition to absence seizures, the tottering mouse also develops motor seizures and ataxia. Point mutations have been identified in the mouse 1A gene in this spontaneous mouse model of absence epilepsy and ataxia.11 The leaner mouse model is characterized by severe progressive ataxia and absence seizures. It results from a mutation that causes a frame shift and premature stop codon in the 1A subunit of the VGCC.11
Homozygous lethargic mice express a phenotype characterized by lethargic behaviour and ataxia, as well as focal motor and absence seizures. A mutation in the gene encoding the VGCC ß4 subunit (Cchb4) has recently been shown to be responsible for the lethargic mouse. The identified mutation comprises a four nucleotide insertion into a splice donor site which results in exon skipping, translational frameshift and protein truncation with loss of the 1-binding site.12 Whilst this mutation might be predicted to produce a truncated ß4 protein that does not possess the 1-binding site, western analysis has demonstrated that there is complete loss of ß4 expression in both cerebellum and forebrain14 and that this is accompanied by decreased expression of N-type VGCCs. Furthermore, there is increased fractional incorporation of the ß1b subunit into N-type VGCCs in the forebrain. This may alter N-type VGCC function either by influencing its biophysical properties or by affecting their modulation by second-messenger systems. The effects of altered ß4 expression on the assembly and function of other types of VGCCs has not yet been examined.
Stargazer is a spontaneous mouse model of epilepsy characterized by absence seizures, a distinctive head movement presumed to be due to vestibular disturbance, and cerebellar dysfunction. The gene defect underlying the stargazer mutant has recently been identified as the insertion of a long transposon into intron-1 of a gene designated Cacng2, which manifests as (incomplete) transcriptional termination.10 Cacng2 has sequence and structural similarity to the skeletal muscle VGCC -subunit, and is expressed exclusively in the brain, where it is enriched in the synaptic plasma membrane. Regional expression is highest in the cerebellum, olfactory bulb, thalamus and hippocampus, similar to that of the 1A subunit, and the stargazer phenotype is similar to that of the tottering and lethargic mice which harbour defects in the 1A and ß4 subunits of the VGCC, respectively. Coexpression of 1A and the protein product of the wild-type Cacng2 gene (stargazin) in BHK cells leads to a shift in the voltage-dependence of 1A VGCC inactivation towards more negative potentials, significantly reducing channel availability at the neuronal resting membrane potential of -70 mV.10 This is consistent with the effect of the skeletal muscle VGCC -subunit on the function of the 1S VGCC. Reduced expression of stargazin, as expected in the stargazer mouse, would result in increased or inappropriate Ca2+ entry into the presynaptic terminal. Together, these data suggest that stargazin is a novel VGCC -subunit.
The stargazer mutant, therefore, predicts an increase in presynaptic Ca2+ entry, whereas reduced Ca2+ entry is expected in the tottering mouse. How such apparently different effects may account for a similar phenotype is not well established, but may relate to the balance between the release of excitatory and inhibitory neurotransmitters or to the effects of downstream second-messenger systems. In this regard, it has been suggested that the effect of the stargazer mutation in reducing the expression of brain-derived neurotrophic factor (BDNF) in the cerebellar granular layer may be responsible for the ataxia manifest in this mouse.10
Discussion
Although VGCCs have now been implicated in a wide range of diseases, the details of our understanding of the precise role that these channels play in disease, is very variable. It is well established that LEMS is an autoimmune disease, and that the presence of anti-VGCC antibodies correlates with disease, and passive transfer studies in mice have established the pathogenic role of these antibodies. There is now good evidence that the disease-causing antibodies specifically target the 1A P/Q-type VGCCs. In FHM, EA-2 and SCA-6, different types of mutations in the 1A gene (CACNA1A) have been shown to segregate with disease. However, there is, as yet, no functional data to demonstrate the precise nature of the functional abnormality of the VGCC which results in the particular disease phenotype. The demonstration that FHM, EA-2 and SCA-6 are all allelic, and that they affect the same gene product which is the target of the immune response in LEMS, raises further questions. If dysfunction of the P/Q-type VGCC underlies all of these disorders, why do the autoantibodies in LEMS not produce migraine, ataxia or spinocerebellar degeneration? Could this simply result from failure of the autoantibodies to cross the blood brain barrier? Similarly, why are none of the symptoms of LEMS present in patients with FHM, EA-2 or SCA-6? The answers to these questions will hopefully follow from elucidation of the distinct functional abnormalities which result from the various mutations in CACNA1A.
The original descriptions of the genetics of EA-2 and SCA-6 suggested that they were phenotypically and genetically distinct disorders. SCA-6, characterized by permanent and progressive cerebellar atrophy and dysfunction, was found to be due to a small CAG repeat expansion. EA-2 results from a truncated protein and manifests as mild and intermittent cerebellar dysfunction. More recently, however, it has been suggested that small CAG expansions in the CACNA1A gene may also be responsible for intermittent cerebellar deficit, and this has raised doubts about the distinction between SCA-6 and EA-2.35
The elucidation of the molecular genetic basis for FHM, and the demonstration of linkage of common forms of migraine with and without aura to the same locus in certain families, raises the intriguing possibility that abnormalities of the same VGCC may underly the more common forms of the disease. Enthusiasm for such prospects, however, should be tempered by the recognition that FHM is genetically heterogeneous, with two further loci having been identified.36,37 Even greater genetic heterogeneity is apparent in the spinocerebellar ataxias, with seven different loci established and further heterogeneity likely. These observations make it difficult to extrapolate from these rare Mendelian disorders to the more common complex traits of sporadic disease.
The observation that abnormalities of the VGCC complex underlie the absence epilepsy of the tottering, leaner, lethargic and stargazer mice raises the exciting prospect that similar dysfunction may contribute to absence epilepsy in humans. This possibility, however, is perhaps at variance with prevailing views about the pathogenesis of absence epilepsy. Epileptic seizures are thought to result from an altered network property of neuronal circuits that result in intermittent, synchronized bursting of neurons separated by periods of normal function. The evidence suggests a central role for thalamocortical circuits in the genesis of bilateral cortical spike and wave discharges,38 and low-threshold T-type VGCCs are thought to play a critical role in generating the thalamic activity which underlies these discharges.39 The human T-type 1G gene has recently been cloned, and its distribution in the brain is wide, with relatively high expression in the diencephalon.40 These findings facilitate further investigation of the 1G gene as a candidate in human absence epilepsy.
Conclusion
Dysfunction of a wide array of ion channels underlies a large number of neurological and non-neurological diseases. This article has focused on those disorders characterized by voltage-gated calcium channel dysfunction. Specifically, dysfunction of the P/Q-type VGCC is implicated in LEMS, FHM, EA2, SCA6 and in a spontaneous mouse model of epilepsy. Different L-type VGCC are dysfunctional in the muscular dysgenesis mouse, in hypokalaemic period paralysis, malignant hyperthermia and X-linked congenital stationary night blindness.
Specific ligands are available for studying many of the different types of VGCCs. L-type VGCC antagonists are already well-established agents in the treatment of ischaemic heart disease and hypertension. Specific agonists and antagonists are already available for the in vitro investigation of some of the other types of VGCCs. The development of such agents for clinical use may open up new therapeutic possibilities for the treatment of the rare diseases discussed above, but also for the more common neurological conditions such as migraine and epilepsy.
Acknowledgements
I am grateful for the helpful comments made by an anonymous referee.
References
1. Choi DW. Calcium: still center-stage in hypoxic-ischaemic neuronal death. Trends Neurosci 1995; 18:58–60.[Web of Science][Medline]
2. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996; 87:543–52.[Web of Science][Medline]
3. Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha-1A-voltage-dependent calcium channel. Nature Genetics 1997; 15:62–8.[Web of Science][Medline]
4. Lang B, Newsom-Davis J, Wray D. Autoimmune aetiology for myasthenic (Eaton-Lambert) syndrome. Lancet 1981; 2:224–6.[Web of Science][Medline]
5. Ptacek L, Tawil R, Griggs R, et al. Dihydropyridine receptor mutations cause hypokalaemic periodic paralysis. Cell 1994; 77:863–8.[Web of Science][Medline]
6. Strom T, Nyakatura G, Apfelstedt-Sylla E, et al. An L-type calcium channel gene mutated in incomplete X-linked congenital stationary night blindness. Nature Genetics 1998; 19:260–3.[Web of Science][Medline]
7. Bech-Hansen N, Naylor M, Maybaum T, et al. Loss-of-function mutations in a calcium-channel alpha-1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nature Genetics 1998; 19:264–7.[Web of Science][Medline]
8. Smith GR, Hamilton S, Hofmann F, et al. Serum antibodies to L-type calcium channels in patients with amyotrophic lateral sclerosis. N Engl J Med 1992; 327:1721–8.[Abstract]
9. Vincent A, Drachman D. Amytrophic lateral sclerosis and antibodies to voltage-gated calcium channels—new doubts. Ann Neurol 1996; 40:691–3.[Web of Science][Medline]
10. Letts VA, Felix R, Biddlecome GH, et al. The mouse stargazer gene encodes a neuronal Ca2+-channel gamma subunit. Nature Genetics 1998; 19:340–7.[Web of Science][Medline]
11. Fletcher CF, Lutz CM, O'Sullivan TN, et al. Absence epilepsy in tottering mutant mice is association with calcium channel defects. Cell 1996; 87:607–17.[Web of Science][Medline]
12. Burgess DL, Jones JM, Meisler M, Noebels JL. Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the Lethargic (1h) mouse. Cell 1997; 88:385–92.[Web of Science][Medline]
13.
Chaudhari N. A single nucleotide deletion in the skeletal muscle-specific calcium channel transcript of muscular dysgenesis (mdg) mice. J Biol Chem 1992; 267:25636–9.
14.
McEnery MW, Copeland TD, Vance CL. Altered expression and assembly of N-type calcium channel alpha-1B and beta subunits in epileptic lethargic (1h/1h) mouse. J Biol Chem 1998; 273:21435–8.
15. McCleskey EW. Calcium channels: cellular roles and molecular mechanisms. Curr Opin Neurobiol 1994; 4:304–12.[Medline]
16. Perez-Reyes E, Schneider T. Molecular biology of calcium channels. Kidney Int 1995; 48:1111–24.[Web of Science][Medline]
17. Walker D, De Waard M. Subunit interaction sites in voltage-dependent Ca2+ channels: role in channel function. Trends Neurosci 1998; 21:148–54.[Web of Science][Medline]
18. Dunlap K, Luebke JI, Turner TJ. Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci 1995; 18:89–98.[Web of Science][Medline]
19.
Protti DA, Reisin R, Mackindley AT, Uchitel OD. Calcium channel blockers and transmitter release at the normal human neuromuscular junction. Neurology 1996; 46:1391–6.
20. Motomura M, Lang B, Johnston I, Palace J, Vincent A, Newsom-Davis J. Incidence of serum anti-P/Q type and anti-N type calcium channel auto-antibodies in the Lambert-Eaton myasthenic syndrome. J Neurol Sci 1997; 147:35–42.[Web of Science][Medline]
21.
Motomura M, Johnston I, Lang B, Vincent A, Newsom-Davis J. An improved diagnostic assay for Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiat 1995; 58:85–7.
22. Verschuuren J, Dalmau J, Tunkel R, et al. Antibodies against the calcium channel beta-subunit in Lambert-Eaton myasthenic syndrome. Neurology 1998; 50:475–9.[Abstract]
23. Fukuoka T, Engel A, Lang B, Newsom-Davis J, Prior L, Wray D. Lambert-Eaton myasthenic syndrome I. Early morphological effects of IgG on the presynaptic membrane active zones. Ann Neurol 1987; 22(2):193–9.[Web of Science][Medline]
24. Pinto A, Gillard S, Moss F, et al. Human autoantibodies specific for the alpha-1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons. Proc Nat Acad Sci USA 1998; 95:8238–33.
25. Waterman S, Lang B, Newsom-Davis J. Effect of Lambert-Eaton myasthenic syndrome antibodies on autonomic nerves in the mouse. Ann Neurol 1997; 42:147–56.[Web of Science][Medline]
26.
Otsu K, Nishida K, Kimura Y. The point mutation Arg615-to-Cys in the Ca2+ release channel of skeletal sarcoplasmic reticulum is responsible for hypersensitivity to caffeine and halothane in malignant hyperthermia. J Biol Chem 1994; 269:9413–15.
27. Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant hyperthermia susceptibility is associated with a mutation of the alpha-1 subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet 1997; 60:1316–25.[Web of Science][Medline]
28.
Iles D, Lehmann-Horn F, Scherer S. Localization of the gene encoding the alpha-2-delta subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families. Hum Mol Genet 1994; 3:969–75.
29. Diriong S, Lory P, Williams M, Ellis S, Harpold M, Taviaux S. Chromosomal localisation of the human genes for alpha 1A, alpha 1B and alpha 1E voltage-dependent Ca2+ channel subunits. Genomics 1995; 30(3):605–9.[Web of Science][Medline]
30. May A, Ophoff RA, Terwindt GM, et al. Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura. Hum Genet 1995; 96:604–8.[Web of Science][Medline]
31. Schmitz Y, Witkovsky P. Dependence of photoreceptor glutamate release on a dihydropyridine-sensitive L-type calcium channel. Neuroscience 1997; 78:1209–16.[Web of Science][Medline]
32. Arsac C, Raymond C, Martin-Moutot N, et al. Immunoassays fail to detect antibodies against neuronal calcium channels in amyotrophic lateral sclerosis. Ann Neurol 1996; 40:695–700.[Web of Science][Medline]
33.
Uchitel OD, Appel SH, Crawford F, Sczcupak L. Immunoglobulins from amyotrophic lateral sclerosis patients enhance spontaneous transmitter release from motor-nerve terminals. Proc Nat Acad Sci USA 1988; 85:7371–4.
34.
Delbono O, Garcia J, Appel SH, Stefani E. Calcium current and charge movement of mammalian muscle: action of amyotrophic lateral sclerosis immunoglobulins. J Physiol 1991; 444:723–42.
35.
Jodice C, Mantuano E, Veneziano L, et al. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Hum Mol Genet 1997; 6:1973–8.
36. Ducros A, Joutel A, Vahedi K, et al. Mapping of a second locus for familial hemiplegic migraine to 1q21–q23 and evidence of further heterogeneity. Ann Neurol 1997; 42:885–90.[Web of Science][Medline]
37.
Gardner K, Barmada M, Ptacek LJ, Hoffman EP. A new locus for hemiplegic migraine maps to chromosome 1q31. Neurology 1997; 49:1231–8.
38. Snead O. Basic mechanisms of generalised absence seizures. Ann Neurol 1995; 37:146–57.[Web of Science][Medline]
39. Tsakiridou E, Bertollini L, de Curtis M, Avanzini G, Pape H. Selective increase in T-type calcium conductance of reticular thalmic neurons in the rat model of absence epilepsy. J Neurosci 1995; 15:3110–17.[Abstract]
40. Perez-Reyes E, Cribbs LL, Daud A, et al. Molecular characterisation of a neuronal low-voltage-activated T-type calcium channel. Nature 1998; 391:896–9.[Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Benatar Neurological potassium channelopathies QJM, December 1, 2000; 93(12): 787 - 797. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||