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• W3023686067 abstract "Calcium channelopathies. Calcium is an important intracellular signaling molecule, and altered calcium channel function can cause widespread cellular changes. Genetic mutations in calcium channels that cause what appear to be trivial alterations of calcium currents in vitro can result in serious diseases in muscles and the nervous system. This article reviews calcium channelopathies in humans and mice. Calcium channelopathies. Calcium is an important intracellular signaling molecule, and altered calcium channel function can cause widespread cellular changes. Genetic mutations in calcium channels that cause what appear to be trivial alterations of calcium currents in vitro can result in serious diseases in muscles and the nervous system. This article reviews calcium channelopathies in humans and mice. Mutations of genes encoding calcium channels are rapidly being identified as causing a diverse group of nerve and muscle diseases. These mutations have been identified in humans, mice and other organisms. In this review, we will summarize calcium channelopathies of humans and mice. For basic scientists interested in calcium channels, the existence of disease-causing mutations raises the hope that their investigations will ultimately have clinical significance. Additionally, the disease-causing mutations may provide new insight into the cell biological roles of calcium channels as well as into relationships between structure and function. However, the calcium channelopathies differ from those of voltage-gated sodium and potassium channels, in which altered electrical excitability of nerve and muscle can be clearly understood in terms of altered biophysical properties of the channels. Since calcium is an important intracellular signaling molecule, altered calcium channel function can give rise to widespread changes in cellular function. Indeed, serious diseases result from mutations that cause trivial alterations of calcium currents analyzed in vitro. Thus, clearly we have much to learn about the biological roles of calcium channels. All voltage-gated calcium channels contain an α1 subunit and most have associated auxiliary subunits. The α1 subunit has four homologous repeats (I to IV), each of which has six membrane-spanning segments (S1 to S6; Figure 1). The extracellular loops that connect the S5 and S6 segments of each repeat contribute to the formation of the ion-conducting pore, and the S4 segments (which contain basic residues at every third position) are responsible for “sensing” the changes of membrane potential that cause the channel to “gate” between closed, open and inactivated states. In addition to carrying out the principle channel functions of gating and permeation, the α1 subunit contains the binding sites for calcium channel agonists and antagonists. Currently, 10 calcium channel α1 subunits have been cloned and sequenced: α1A, α1B, α1C, α1D1Snutch T.P. Leonard J.P. Gilbert M.M. Lester H.A. Davidson N. Rat brain expresses a heterogeneous family of calcium channels.Proc Natl Acad Sci USA. 1990; 87: 3391-3395Crossref PubMed Scopus (216) Google Scholar, α1E2Soong T.W. Stea A. Hodson C.D. Dubel S.J. Vincent S.R. Snutch T.P. Structure and functional expression of a member of the low voltage-activated calcium channel family.Science. 1993; 260: 1133-1136Crossref PubMed Scopus (425) Google Scholar, α1F3Bech-Hansen N.T. Naylor M.J. Maybaum T.A. Pearce W.G. Koop B. Fishman G.A. Mets M. Musarella M.A. Boycott K.M. Loss-of-function mutations in a calcium-channel α1-subunit gene in Xp11.23 cause incomplete X-linked stationary night blindness.Nat Genet. 1998; 19: 264-267Crossref PubMed Scopus (401) Google Scholar,4Strom T.M. Nyakatura G. Apefelstedt-Sylla E. Hellebrand H. Lorenz B. Weber B.H.F. Wutz K. Gutwillinger N. Ruther K. Drescher B. Sauer C. Zrenner E. Meitinger T. Rosenthal A. Meindl A. A L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness.Nature Genet. 1998; 19: 260-263Crossref PubMed Scopus (373) Google Scholar, α1G5Perez-Reyes E. Cribbs L.L. Daud A. Lacerda A.E. Barclay J. Williamson M.P. Fox M. Rees M. Lee J-H. Molecular characterization of a neuronal low voltage-activated T-type calcium channel.Nature. 1998; 391: 896-900Crossref PubMed Scopus (619) Google Scholar, α1H6Cribbs L.L. Lee J-H. Yang J. Satin J. Zhang Y. Daud A. Barclay J. Williamson M.P. Fox M. Rees M. Perez-Reyes E. Cloning and characterization of α1H from human heart, a member of the T-type calcium channel gene family.Circ Res. 1998; 83: 103-109Crossref PubMed Scopus (497) Google Scholar, α1I7Lee J-H. Daud A.N. Cribbs L.L. Lacerda A.E. Pereverzev A. Klockner U. Schneider T. Perez-Reyes E. Cloning and expression of a novel member of the low voltage-activated T-type calcium channel family.J Neurosci. 1999; 19: 1912-1921Crossref PubMed Google Scholar, and α1S8Tanabe T. Takeshima H. Mikami A. Flockerzi V. Takahashi H. Kangawa K. Kojima M. Matsuo H. Hirose T. Numa S. Primary structure of the receptor for calcium channel blockers from skeletal muscle.Nature. 1987; 328: 313-318Crossref PubMed Scopus (931) Google Scholar. Many of these α1 subunits have been associated with specific types of calcium currents, which were first described on the basis of pharmacological and biophysical criteria. Of those discussed in this review, α1C and α1S correspond to L-type calcium channels, originally defined on the basis of pharmacological sensitivity to dihydropyridines. Because of the tissues in which they are highly expressed, α1C and α1S are often referred to as cardiac and skeletal muscle isoforms, respectively. Based on its amino acid sequence, α1F is also an L-type channel, which is highly expressed in retina3Bech-Hansen N.T. Naylor M.J. Maybaum T.A. Pearce W.G. Koop B. Fishman G.A. Mets M. Musarella M.A. Boycott K.M. Loss-of-function mutations in a calcium-channel α1-subunit gene in Xp11.23 cause incomplete X-linked stationary night blindness.Nat Genet. 1998; 19: 264-267Crossref PubMed Scopus (401) Google Scholar,4Strom T.M. Nyakatura G. Apefelstedt-Sylla E. Hellebrand H. Lorenz B. Weber B.H.F. Wutz K. Gutwillinger N. Ruther K. Drescher B. Sauer C. Zrenner E. Meitinger T. Rosenthal A. Meindl A. A L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness.Nature Genet. 1998; 19: 260-263Crossref PubMed Scopus (373) Google Scholar. The α1A channel is expressed in cell bodies, dendrites and presynaptic terminals of most central neurons9Westenbroek R.E. Sakurai T. Elliott E.M. Hell J.W. Starr T.V.B. Snutch T.P. Catterall W.A. Immunochemical identification and subcellular distribution of the α1A subunits of brain calcium channels.J Neurosci. 1995; 15: 6403-6418Crossref PubMed Google Scholar with highest expression in cerebellar neurons9Westenbroek R.E. Sakurai T. Elliott E.M. Hell J.W. Starr T.V.B. Snutch T.P. Catterall W.A. Immunochemical identification and subcellular distribution of the α1A subunits of brain calcium channels.J Neurosci. 1995; 15: 6403-6418Crossref PubMed Google Scholar, 10Mori Y. Friedrich T. Kim M-S. Mikami A. Nakai J. Ruth P. Bosse E. Hofmann F. Flockerzi V. Furuichi T. Mikoshiba K. Imoto K. Tanabe T. Numa S. Primary structure and functional expression from complementary DNA of a brain calcium channel.Nature. 1991; 350: 398-402Crossref PubMed Scopus (695) Google Scholar, 11Sather W.A. Tanabe T. Zhang J-F. Mori Y. Adams M.E. Tsien R.W. Distinctive biophysical and pharmacological properties of Class A (B1) calcium channel α1 subunits.Neuron. 1993; 11: 291-303Abstract Full Text PDF PubMed Scopus (378) Google Scholar, 12Starr T.V.B. Prystay W. Snutch T.P. Primary structure of a calcium channel that is highly expressed in the rat cerebellum.Proc Natl Acad Sci USA. 1991; 88: 5621-5625Crossref PubMed Scopus (225) Google Scholar, 13Stea A. Tomlinson W.J. Soong T.W. Bourinet E. Dubel S.J. Vincent S.R. Snutch T.P. 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. 1994; 91: 10576-10580Crossref PubMed Scopus (301) Google Scholar and produces current kinetically and pharmacologically (sensitive to ω-Aga-IVA) defined as P/Q-type14Bourinet E. Soong T.W. Sutton K. Slaymaker S. Mathews E. Monteil A. Zamponi G.W. Nargeot J. Snutch T.P. Splicing of the α1A subunit gene generates phenotypic variants of P- and Q-type calcium channels.Nature Neurosci. 1999; 2: 407-415Crossref PubMed Scopus (354) Google Scholar. The α1B channel is primarily expressed in dendrites and nerve terminals15Westenbroek R.E. Hell J.W. Warner C. Dubel S.J. Snutch T.P. Catterall W.A. Biochemical properties and subcellular distribution of an N-type calcium channel α1 subunit.Neuron. 1992; 9: 1099-1115Abstract Full Text PDF PubMed Scopus (477) Google Scholar with a wide distribution throughout the brain16Dubel S.J. Starr T.N.B. Hell J. Ahlijanian M.K. Enyeart J.J. Catterall W.A. Snutch T.P. Molecular cloning of the α-1 subunit of an ω-conotoxin-sensitive calcium channel.Proc Natl Acad Sci USA. 1989; 89: 5058-5062Crossref Scopus (274) Google Scholar and is blocked by ω-CTXGVIA17Williams M.E. Brust P.F. Feldman D.H. Patthi S. Simerson S. Maroufi A. McCue A.F. Velicelebi G. Ellis S.B. Harpold M.M. Structure and functional expression of an ω-conotoxin-sensitive human N-type calcium channel.Science. 1992; 257: 389-395Crossref PubMed Scopus (408) Google Scholar, a defining characteristic of N-type current. In addition to the α1 subunit, most calcium channels contain the auxiliary subunits α2-αδwhich is proposed to have a single membrane-spanning segment, and β, which is entirely cytoplasmic. Some channels (α1S) have been shown to contain a γ subunit, which is thought to have four membrane-spanning segments. The auxiliary subunits modify channel expression, voltage-dependence and kinetics, with the most pronounced effects arising from the β subunit [reviewed in18Walker D. De Waard M. Subunit interaction sites in voltage-dependent Ca2+ channels: Role in channel function.Trends Neurosci. 1993; 21: 148-154Abstract Full Text Full Text PDF Scopus (312) Google Scholar. Neuronal calcium channels have many cellular functions including: control of neurotransmitter release, regulation of gene expression, integration and propagation of postsynaptic signals, and neurite outgrowth. In addition to altering these signaling pathways, calcium channel mutations could in principle cause cytotoxicity. In particular, both increased [reviewed in19Choi D.W. Calcium-mediated neurotoxicity: Relationship to specific channel types and role in ischemic damage.Trends Neurosci. 1988; 11: 465-469Abstract Full Text PDF PubMed Scopus (1584) Google Scholar and decreased20Koh J.Y. Cotman C.W. Programmed cell death: Its possible contribution to neurotoxicity mediated by calcium channel antagonists.Brain Res. 1992; 587: 233-240Crossref PubMed Scopus (103) Google Scholar, 21Koike T. Martin D.P. Johnson Jr, Em Role of Ca2+ channels in the ability of membrane depolarization to prevent neuronal death induced by trophic-factor deprivation: Evidence that levels of internal Ca2+ determine nerve growth factor dependence of sympathetic ganglion cells.Proc Natl Acad Sci USA. 1989; 86: 6421-6425Crossref PubMed Scopus (368) Google Scholar, 22McCaslin P.P. Smith T.G. Low calcium-induced release of glutamate results in autotoxicity of cerebellar granule cells.Brain Res. 1990; 53: 280-285Crossref Scopus (25) Google Scholar intracellular Ca2+ have been reported to be cytotoxic to neurons. Human incomplete X-linked congenital stationary night blindness (incomplete xlCSNB) is a heterogeneous, nonprogressive disorder with impairment of night vision and variably reduced day vision, which is thought to result from altered synaptic transmission from photoreceptor cells to second-order neurons. Incomplete xlCSNB has been linked to mutations in the α1F subunit of a retinal L-type channel. These mutations include missense, deletions, and frameshifts with premature stops Figure 13Bech-Hansen N.T. Naylor M.J. Maybaum T.A. Pearce W.G. Koop B. Fishman G.A. Mets M. Musarella M.A. Boycott K.M. Loss-of-function mutations in a calcium-channel α1-subunit gene in Xp11.23 cause incomplete X-linked stationary night blindness.Nat Genet. 1998; 19: 264-267Crossref PubMed Scopus (401) Google Scholar,4Strom T.M. Nyakatura G. Apefelstedt-Sylla E. Hellebrand H. Lorenz B. Weber B.H.F. Wutz K. Gutwillinger N. Ruther K. Drescher B. Sauer C. Zrenner E. Meitinger T. Rosenthal A. Meindl A. A L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness.Nature Genet. 1998; 19: 260-263Crossref PubMed Scopus (373) Google Scholar. The effects of these mutations on channel function have not yet been characterized. However, since synaptic transmission from photoreceptor cells to second-order retinal neurons is mediated by L-type current23Schmitz Y. Witzovsky P. Dependence of photoreceptor glutamate release on a dihydropyridine-sensitive calcium channel.Neuroscience. 1997; 78: 1209-1216Crossref PubMed Scopus (114) Google Scholar, it seems likely that α1F is at least partially responsible for this transmission and that the α1F mutations may impair transmission. Mutations in the α1A calcium channel subunit have been shown to produce the human autosomal-dominant neurological disorders of familial hemiplegic migraine, episodic ataxia type-2, spinocerebellar ataxia-6, and episodic-and-progressive ataxia. Defects in the gene encoding the α1A calcium channel subunit are also responsible for the recessively inherited phenotypes of tottering (tg) and leaner (tgla) in mice. In each of these diseases, alteration of a single gene results in a host of neurological aberrations including abnormal cerebellar function and cerebellar atrophy. In general, α1A mutations have pronounced effects on the cerebellum, which is not surprising given that α1A is highly expressed in cerebellar neurons. In particular, about 90% of rat Purkinje cell calcium current is blocked with high affinity by the toxin ω-Aga-IVA24Mintz I.M. Adams M.E. Bean B.P. P-type calcium channels in rat central and peripheral neurons.Neuron. 1992; 9: 85-95Abstract Full Text PDF PubMed Scopus (630) Google Scholar, indicating that this large fraction of current arises from α1A14Bourinet E. Soong T.W. Sutton K. Slaymaker S. Mathews E. Monteil A. Zamponi G.W. Nargeot J. Snutch T.P. Splicing of the α1A subunit gene generates phenotypic variants of P- and Q-type calcium channels.Nature Neurosci. 1999; 2: 407-415Crossref PubMed Scopus (354) Google Scholar. Familial hemiplegic migraine (FHM) is associated with headaches accompanied by aura and hemiparesis (which is typically transient lasting hours to days), ataxia and nystagmus. In some families, cerebellar atrophy may also occur. The onset of this disorder is usually in childhood or adolescence. Genetic studies of FHM patients have identified four missense mutations causing defects in the α1A subunit: R192Q, T666M, V714A, and I1811L25Ophoff R.A. Terwindt G.M. Vergouwe M.N. van Eijk R. Oefner P.J. Hoffman S.M.G. Lamberdin J.E. Mohrenweiser H.W. Bulman D.E. Ferrari M. Hann J. Lindhout D. van Ommen G-JB. Hofker M.H. Ferrari M.D. Frants R.R. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.Cell. 1996; 87: 543-552Abstract Full Text Full Text PDF PubMed Scopus (2030) Google Scholar. These missense mutations affect highly conserved residues26Fujita Y. Mynlieff M. Dirksen R.T. Kim M-S. Niidome T. Nakai J. Friedrich T. Iwabe N. Miyata T. Furuichi T. Furutama D. Mikoshiba K. Mori Y. Beam K.G. Primary structure and functional expression of the ω-conotoxin-sensitive N-type calcium channel from rabbit brain.Neuron. 1993; 10: 585-598Abstract Full Text PDF PubMed Scopus (203) Google Scholar and are widely distributed throughout the protein Figure 2. The effects of these four FHM mutations on calcium currents have been studied by two groups. The first group27Kraus R.L. Sinnegger M.J. Glossmann H. Hering S. Stressnig J. Familial hemiplegic migraine mutations change α1A Ca2+ channel kinetics.J Biol Chem. 1998; 273: 5586-5590Crossref PubMed Scopus (172) Google Scholar introduced the mutations into the cDNA encoding an isoform (BI-2) of rabbit α1A and coexpressed it in Xenopus oocytes with the α2-αδ and β1a subunits. The second group28Hans M. Luvisetto S. Williams M.E. Spagnolo M. Urrutia A. Tottene A. Brust P.F. Johnson E.C. Harpold M.M. Stauderman K.A. Pietrobon D. Functional consequences of mutations in the human α1A calcium channel subunit linked to familial hemiplegic migraine.J Neurosci. 1999; 19: 1610-1619Crossref PubMed Google Scholar introduced the mutations into human α1A-2 and coexpressed it in HEK293 cells with α2b-αδ and either β2e or β3a. Both groups found that: (1) R192Q produced little in the way of biophysical alterations; (2) T666M slowed recovery from inactivation; and (3) V714A and I1819L both accelerated recovery from inactivation. Additionally, Hans et al found that: (1) channel density in HEK293 cells was increased for R192Q and decreased for the other three mutants; (2) that channel open probability was increased for R192Q, V714A and I1819L; and (3) single channel conductance was decreased for T666M and V714A28Hans M. Luvisetto S. Williams M.E. Spagnolo M. Urrutia A. Tottene A. Brust P.F. Johnson E.C. Harpold M.M. Stauderman K.A. Pietrobon D. Functional consequences of mutations in the human α1A calcium channel subunit linked to familial hemiplegic migraine.J Neurosci. 1999; 19: 1610-1619Crossref PubMed Google Scholar. Thus, some of these mutations would be expected to increase calcium entry and some would be expected to decrease it. Obviously, it is difficult to explain why this diverse set of changes in channel properties all produce the FHM phenotype. Episodic ataxia-2 (EA-2) is associated with ataxia, nystagmus, dysarthria and vertigo. Cerebellar atrophy is common, and 50% of EA-2 patients report migraine-like symptoms. The ataxia is provoked by stress, exercise or fatigue and lasts hours to days. Onset of this disorder is usually late childhood or adolescence. Three mutations causing EA-2 have been identified in α1A Figure 2. The first is a single nucleotide deletion that causes a frameshift within IIIS1 and translational stop shortly thereafter25Ophoff R.A. Terwindt G.M. Vergouwe M.N. van Eijk R. Oefner P.J. Hoffman S.M.G. Lamberdin J.E. Mohrenweiser H.W. Bulman D.E. Ferrari M. Hann J. Lindhout D. van Ommen G-JB. Hofker M.H. Ferrari M.D. Frants R.R. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.Cell. 1996; 87: 543-552Abstract Full Text Full Text PDF PubMed Scopus (2030) Google Scholar, the second is a single base mutation that introduces a premature stop into IIIS1-S2 linker29Yue Q. Jen J.C. Thwe M.M. Nelson S.F. Baloh R.W. De novo mutation in CACNA1A caused acetazolamide-responsive episodic ataxia.Am J Med Genet. 1998; 77: 298-301Crossref PubMed Scopus (70) Google Scholar, and the third alters an intronic 5′ splice junction causing translational stop within IIIS225Ophoff R.A. Terwindt G.M. Vergouwe M.N. van Eijk R. Oefner P.J. Hoffman S.M.G. Lamberdin J.E. Mohrenweiser H.W. Bulman D.E. Ferrari M. Hann J. Lindhout D. van Ommen G-JB. Hofker M.H. Ferrari M.D. Frants R.R. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.Cell. 1996; 87: 543-552Abstract Full Text Full Text PDF PubMed Scopus (2030) Google Scholar. One might expect that with such mutations there would be little or no mutant protein (effectively genetic nulls), which seemingly contradicts dominant inheritance unless there is haploinsufficiency. Alternatively, the prematurely truncated protein could be a dominant negative if it acted as a molecular sink for cytoplasmic proteins important for calcium channel localization and function. Autosomal dominant spinocerebellar ataxia 6 (SCA6) is dominantly inherited. It is characterized by ataxia, nystagmus, dysarthria, and neuronal loss in the cerebellum (Purkinje and granule cells) and the dentate and inferior olivary nuclei. Symptoms initially appear at 40 to 50 years of age and become progressively more severe. Analyses of patients with SCA6 demonstrated the presence of an expanded CAG repeat (normal individuals having 4 to16 CAGs and affected individuals having 21 to 27 CAGs), which is much smaller than the trinucleotide repeats associated with other neurodegenerative disorders30Zhuchenko O. Bailey J. Bonnen P. Ashizawa T. Stockton D.W. Amos C. Dobyns W.B. Subramony S.H. Zoghbi H.Y. Lee C.C. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel.Nat Genet. 1997; 15: 62-69Crossref PubMed Scopus (1373) Google Scholar. Similar CAG expansions have been observed in individuals having symptoms of both SCA6 and EA-231Geschwind D.H. Perlman S. Figueroa K.P. Karrim J. Baloh R.W. Pulst S.M. Spinocerebellar ataxia type 6: Frequency of the mutation and genotype-phenotype correlations.Neurology. 1997; 49: 1247-1251Crossref PubMed Scopus (160) Google Scholar or only of EA-232Jodice C. Mantuano E. Veneziano L. Trettel F. Sabbadini G. Calandriello L. Francia A. Spadaro M. Pierelli F. Salvi F. Ophoff R.A. Frants R.R. Frontali M. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p.Hum Molec Genet. 1997; 6: 1973-1978Crossref PubMed Scopus (243) Google Scholar, which may indicate that the two diseases actually represent a continuum of symptoms. The CAG expansion in SCA6 introduces polyglutamines at a position approximately 100 amino acids from the carboxyl terminal Figure 2. Increased repeat size is associated with both greater disease severity and earlier onset. The pathological consequences of many diseases involving trinucleotide repeats are thought to be related to altered stability of the mutant protein, toxic metabolic breakdown products of the glutamines, or the interaction of the CAG repeats with proteins required for processing RNA. Alternatively, the polyglutamine expansion causing SCA6 might alter the biophysical properties, expression or protein–protein interactions of α1A. Episodic and progressive ataxia has some clinical attributes which overlap with SCA6 and EA-2. Distinguishing features include earlier onset (5 to 15 years of age), more prominent cerebellar atrophy and, unlike EA-2, insensitivity to treatment with acetazolamide. The disease has been associated with a missense mutation (G293R; Figure 2) of a conserved amino acid in the S5-S6 linker (pore region) of repeat I of α1A33Yue Q. Jen J.C. Nelson S.F. Baloh R.W. Progressive ataxia due to a missense mutation in a calcium-channel gene.Am J Hum Genet. 1997; 61: 1078-1087Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar. As a recessively inherited neurological disease of mice, tottering (tg) is characterized by seizures (absence and focal motor) and mild ataxia34Noebels J.L. A single gene error of noradrenergic axon growth synchronizes central neurones.Nature. 1984; 310: 409-411Crossref PubMed Scopus (115) Google Scholar. There is minor diffuse loss of cerebellar granule and Purkinje cells, an increased density of noradrenergic fibers from the locus coeruleus, and abnormal persistence of tyrosine hydroxylase expression in Purkinje cells35Hess E.J. Wilson M.C. Tottering and leaner mutations perturb transient developmental expression of tyrosine hydroxylase in embryologically distinct Purkinje cells.Neuron. 1991; 6: 123-132Abstract Full Text PDF PubMed Scopus (131) Google Scholar. Tottering results from a single nucleotide change that substitutes leucine for proline (P601L; Figure 2) in the IIS5-S6 linker of α1A36Fletcher C.F. Lutz C.M. O'sullivan T.N. Shaughnessy Jr, Jd Hawkes R. Frankel W.N. Copeland N.G. Jenkins N. Absence epilepsy in tottering mutant mice is associated with calcium channel defects.Cell. 1996; 87: 607-617Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar,37Doyle J. Ren X. Lennon G. Stubbs L. Mutations in the Cacnl1a4 calcium channel gene are associated with seizures, cerebellar degeneration, and ataxia in tottering and leaner mutant mice.Mamm Genome. 1997; 8: 113-120Crossref PubMed Scopus (109) Google Scholar. In BHK cells heterologously expressing the tg mutated channel, gating is unchanged but current density is reduced by 56%; calcium channel currents are also reduced in cerebellar Purkinje cells of tg mice38Wakamori M. Yamazaki K. Matsunodaira H. Teramoto T. Tanaka I. Niidome T. Sawada K. Nishizawa Y. Sekiguchi N. Mori E. Mori Y. Imoto K. Single tottering mutations responsible for the neuropathic phenotype of the P-type calcium channel.J Biol Chem. 1998; 273: 34857-34867Crossref PubMed Scopus (190) Google Scholar. The amplitude of single channel currents in the BHK cells is normal38Wakamori M. Yamazaki K. Matsunodaira H. Teramoto T. Tanaka I. Niidome T. Sawada K. Nishizawa Y. Sekiguchi N. Mori E. Mori Y. Imoto K. Single tottering mutations responsible for the neuropathic phenotype of the P-type calcium channel.J Biol Chem. 1998; 273: 34857-34867Crossref PubMed Scopus (190) Google Scholar. The reduction in current density may be a consequence of reduced channel open probability since cerebellar α1A mRNA is normal37Doyle J. Ren X. Lennon G. Stubbs L. Mutations in the Cacnl1a4 calcium channel gene are associated with seizures, cerebellar degeneration, and ataxia in tottering and leaner mutant mice.Mamm Genome. 1997; 8: 113-120Crossref PubMed Scopus (109) Google Scholar. The leaner (tgla) is another recessively inherited disorder of mice that is characterized by severe ataxia34Noebels J.L. A single gene error of noradrenergic axon growth synchronizes central neurones.Nature. 1984; 310: 409-411Crossref PubMed Scopus (115) Google Scholar and substantial loss of cerebellar Purkinje and granule cells39Herrup K. Wilczynski S.L. Cerebellar cell degeneration in the leaner mutant mouse.Neuroscience. 1982; 7: 2185-2196Crossref PubMed Scopus (152) Google Scholar. The surviving Purkinje cells exhibit aberrant morphology40Heckroth J.A. Abbott L.C. Purkinje cell loss from alternating sagittal zones in the cerebellum of leaner mutant mice.Brain Res. 1994; 658: 93-104Crossref PubMed Scopus (73) Google Scholar. The tgla mutation has been identified as a single nucleotide substitution in a splice donor consensus sequence of the α1A gene, which results either in a short or long isoform. The short isoform has altered sequence that begins at amino acid 1922 (Figure 2; numbered according to the mouse α1A) and terminates 57 amino acids later, and the long isoform has altered sequence that begins at amino acid 1968 and terminates 90 amino acids later36Fletcher C.F. Lutz C.M. O'sullivan T.N. Shaughnessy Jr, Jd Hawkes R. Frankel W.N. Copeland N.G. Jenkins N. Absence epilepsy in tottering mutant mice is associated with calcium channel defects.Cell. 1996; 87: 607-617Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar,37Doyle J. Ren X. Lennon G. Stubbs L. Mutations in the Cacnl1a4 calcium channel gene are associated with seizures, cerebellar degeneration, and ataxia in tottering and leaner mutant mice.Mamm Genome. 1997; 8: 113-120Crossref PubMed Scopus (109) Google Scholar. In Purkinje cells from tgla mice, whole cell calcium current is reduced in amplitude ~65%38Wakamori M. Yamazaki K. Matsunodaira H. Teramoto T. Tanaka I. Niidome T. Sawada K. Nishizawa Y. Sekiguchi N. Mori E. Mori Y. Imoto K. Single tottering mutations responsible for the neuropathic phenotype of the P-type calcium channel.J Biol Chem. 1998; 273: 34857-34867Crossref PubMed Scopus (190) Google Scholar, 41Dove L.S. Abbott L.C. Griffith W.H. Whole-cell and single-channel analysis of P-type calcium currents in cerebellar Purkinje cells of leaner mutant mice.J Neurosci. 1998; 18: 7687-7699Crossref PubMed Google Scholar, 42Lorenzon N.M. Lutz C.M. Frankel M.N. Beam K.G. Altered calcium channel currents in Purkinje cells of the neurological mutant mouse leaner.J Neurosci. 1998; 18: 4482-4489Crossref PubMed Google Scholar. The reduction is specifically in the ω-Aga-IVA-sensitive component of current, and the remaining ω-Aga-IVA-sensitive current has unchanged gating properties42Lorenzon N.M. Lutz C.M. Frankel M.N. Beam K.G. Altered calcium channel currents in Purkinje cells of the neurological mutant mouse leaner.J Neurosci. 1998; 18: 4482-4489Crossref PubMed Google Scholar. Dove, Abbott and Griffith suggest that the reduced current density results from decreased open probability41Dove L.S. Abbott L.C. Griffith W.H. Whole-cell and single-channel analysis of P-type calcium currents in cerebellar Purkinje cells of leaner mutant mice.J Neurosci. 1998; 18: 7687-7699Crossref PubMed Google Scholar. Interestingly, Wakamori et al found that the behavior of short and long tgla isoforms differed38Wakamori M. Yamazaki K. Matsunodaira H. Teramoto T. Tanaka I. Niidome T. Sawada K. Nishizawa Y. Sekiguchi N. Mori E. Mori Y. Imoto K. Single tottering mutations responsible for the neuropathic phenotype of the P-type calcium channel.J Biol Chem. 1998; 273: 34857-34867Crossref PubMed Scopus (190) Google Scholar. In comparison with wild-type α1A expressed in BHK cells, the current density was unchanged for the long isoform although both activation and inactivation were shifted in the depolarizing direction (5 to 10 mV), whereas current density was reduced for the short isoform without any other changes. As is the case for FHM, the relationship between altered channel properties and neuropathology remains unclear. A recessive mouse disorder, lethargic (lh) includes behavioral traits overlapping those of human and murine α1A diseases (ataxia and absence seizures43Sidman R.L. Gree" @default.
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