Kinetic Alterations due to a Missense Mutation in the Na,K-ATPase α2 Subunit Cause Familial Hemiplegic Migraine Type 2

Segall, Laura; Scanzano, Rosemarie; Kaunisto, Mari A.; Wessman, Maija; Palotie, Aarno; Gargus, J. Jay; Blostein, Rhoda

doi:10.1074/jbc.m407471200

Cited by 59 publications

(60 citation statements)

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“…2) have been investigated in HeLa cells expressing recombinant (human or rat) ␣ 2 Na ϩ ,K ϩ -ATPase subunits containing mutations that make the pump insensitive to ouabain, which allows one to distinguish the activity of the exogenous pumps from the endogenous pumps of the cell line. 10,68,69,84,85 Three FHM2 mutations (L764P, W887R, G615R, and also the AHC mutation) produced severe or complete loss-offunction of pump activity, because HeLa cells transfected with the FHM2 mutants showed rapid mortality in the presence of ouabain. 10,69,71 Complete loss of pump activity (as measured by lack of pump current) with unaltered expression in the plasma membrane has been shown for the L764P and W887R mutants expressed in Xenopus ocytes.…”

Section: Figmentioning

confidence: 99%

“…86 In contrast, the other five FHM2 mutants analyzed so far conferred sufficient Na ϩ /K ϩ pump activity to allow survival of HeLa cells although at a reduced rate in the case of the R593W and V628M mutants; survival was similar to that conferred by the WT pump in the case of the T345A, M731T, and R689Q mutants. 68,84,85 However, the T345A mutant had a lower affinity for extracellular K ϩ , which would slow removal of K ϩ from the extracellular space and slow the recovery from neuronal excitation. 84 The M731T and R689Q mutants had a decreased catalytic turnover and increased affinity for extracellular Kϩ, which would also slow extracellular Kϩ clearance in the plausible hypothesis that the lower catalytic turnover overrides the effect of increased Kϩ affinity, at least at high extracellular Kϩ concentrations.…”

Section: Figmentioning

confidence: 99%

“…68,84,85 However, the T345A mutant had a lower affinity for extracellular K ϩ , which would slow removal of K ϩ from the extracellular space and slow the recovery from neuronal excitation. 84 The M731T and R689Q mutants had a decreased catalytic turnover and increased affinity for extracellular Kϩ, which would also slow extracellular Kϩ clearance in the plausible hypothesis that the lower catalytic turnover overrides the effect of increased Kϩ affinity, at least at high extracellular Kϩ concentrations. 85 Impaired clearance of K ϩ and glutamate by astrocytes during cortical neuronal activity, consequent to a decreased number of functional Na ϩ ,K ϩ -ATPases, or a decreased affinity for K ϩ or a decreased catalytic turnover of the ␣ 2 Na ϩ ,K ϩ -ATPase pumps, would depolarize neurons and enhance glutamate concentration in the synaptic cleft, thus impairing recovery from neuronal excitation.…”

Section: Figmentioning

confidence: 99%

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Familial Hemiplegic Migraine

2007

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Summary: Familial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCNA1A, encoding the pore-forming ␣ 1 subunits of the neuronal voltage-gated Ca 2ϩ channels Ca V 2.1 and Na ϩ channels Na V 1.1, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the ␣ 2 subunit of the Na ϩ , K ϩ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHM1 knockin mice and of several FHM mutants in heterologous expression systems (12 FHM1, 8 FHM2, and 1 FHM3). These studies show the following: (1) FHM1 mutations produce gain-of-function of the Ca V 2.1 channel and, as a consequence, increased Ca V 2.1-dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phenomenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the ␣ 2 Na ϩ ,K ϩ -ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na V 1.5 (and presumably Na V 1.1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K ϩ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K ϩ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment.

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Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Familial Hemiplegic Migraine

2007

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“…CACNA1A, encoding the α1 subunit of the neuronal P/Q Ca ++ channel, and ATP1A2, encoding the α2 isoform of the major subunit of the Na,K-ATPase, give rise to FHM1 [OMIM #141500] and FHM2 [OMIM #602481], respectively, and together account for most FHM patients [2,4,5]. The FHM2 mutations produce hypomorphic kinetic alterations in Na/K pump function [6,7], but it remains controversial whether FHM1 mutations are hypermorphic [8] or hypomorphic [9].…”

Section: Introductionmentioning

confidence: 99%

Novel Mutation Confirms Seizure Locus SCN1A is Also Familial Hemiplegic Migraine Locus FHM3

Gargus

Tournay

2007

Pediatric Neurology

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While the gene encoding the neuronal voltage-gated sodium channel, type 1A is a well-recognized target of mutations underlying a spectrum of epilepsy syndromes, and lies within an extended 12 megabase disease-associated haplotype at the Familial Hemiplegic Migraine, type 3 locus, it remains to be confirmed that mutations within this gene itself cause syndromes that include migraine phenotypes. This report presents a family segregating the novel T1174S missense mutation of this gene detected in a heterozygous female child who presented with myoclonus and an abnormal EEG, and in her mother who has an ataxic migraine syndrome similar to that of her own mother. This threegeneration family exhibits the broad phenotypic spectrum of the dominant neuronal hyperexcitability syndromes produced by even a given allele of this sodium channel gene. It also exhibits the second allele of this sodium channel gene associated with a migraine syndrome similar to those caused at the two other Familial Hemiplegic Migraine loci, confirming that this gene itself, not some linked gene, is the Familial Hemiplegic Migraine, type 3 locus.

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“…In the case of the first two of the reported mutations, L764P and W887R, DeFusco et al (7) suggested that the disease is the result of haploinsufficiency because the mutant enzyme does not support the growth of cells in culture. We have since shown that in contrast to cells bearing mutants L764P and W887R, those bearing the T345A replacement had normal growth but showed altered (decreased) K ϩ affinity, thus likely accounting for the disease (8).…”

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Alterations in the α2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2

Segall

Mezzetti

Scanzano

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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A number of missense mutations in the Na,K-ATPase ␣2 catalytic subunit have been identified in familial hemiplegic migraine with aura. Two alleles (L764P and W887R) showed loss-of-function, whereas a third (T345A) is fully functional but with altered Na,KATPase kinetics. This study describes two additional mutants, R689Q and M731T, originally identified by Vanmolkot et al. , which we show here to also be functional and kinetically altered. Both mutants have reduced catalytic turnover and increased apparent affinity for extracellular K ؉ . For both R689Q and M731T, sensitivity to vanadate inhibition is decreased, suggesting that the steadystate E 1 7 E2 poise of the enzyme is shifted toward E1. Whereas the K ATP is not affected by the R689Q replacement, the M731T mutant has an increase in apparent affinity for ATP. Analysis of the structural changes effected by T345A, R689Q, and M731T mutations, based on homologous replacements in the known crystal structure of the sarcoplasmic reticulum Ca-ATPase, provides insights into the molecular bases for the kinetic alterations. It is suggested that the disease phenotype is the consequence of lowered molecular activity of the ␣2 pump isoform due to either decreased K ؉ affinity (T345A) or catalytic turnover (R689Q and M731T), thus causing a delay in extracellular K ؉ clearance and͞or altered localized Ca 2؉ handling͞signaling secondary to reduced activity in colocalized Na ؉ ͞Ca 2؉ exchange.sodium pump kinetics ͉ missense mutations ͉ ATP1A2 gene T he Na,K-ATPase catalyzes the ATP-driven exchange of three intracellular Na ϩ ions for two extracellular K ϩ ions across the plasma membrane of virtually all animal cells and is essential to the maintenance of the electrochemical alkali cation gradients that are dissipated by ion channels in the propagation of action potentials (for recent reviews, see refs. 1 and 2). The catalytic cycle of this P type ion pump involves phosphorylation and dephosphorylation of a conserved aspartate residue in its catalytic ␣ subunit and conformational transitions of phosphoand dephosphoenzyme, commonly referred to as E 1 P 7 E 2 P and E 1 7 E 2 conformational transitions, respectively (see Scheme 1). Four isoforms of ␣ and three isoforms of ␤ have been described thus far. All are distributed in a tissue-and developmentally dependent manner. In adult mammals, ␣2 is located principally in skeletal muscle and brain, in particular in glial cells, and, to a lesser extent, in heart, adipocytes, and the eye (see refs. 3-6).The discovery of the association of missense mutations in the ATP1A2 gene on chromosome 1q23 that encodes the Na,KATPase ␣2 isoform with familial hemiplegic migraine (FHM) has been an important breakthrough in that it reflects a disease caused by a kinetically altered sodium pump and is therefore an important lead in migraine pathophysiology. Although a migraine is a common polygenic disorder, FHM is a rare autosomal dominant form of migraine with aura and is usually additionally associated with hemiparesis and other clinical features ...

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Kinetic Alterations due to a Missense Mutation in the Na,K-ATPase α2 Subunit Cause Familial Hemiplegic Migraine Type 2

Cited by 59 publications

References 33 publications

Familial Hemiplegic Migraine

Familial Hemiplegic Migraine

Novel Mutation Confirms Seizure Locus SCN1A is Also Familial Hemiplegic Migraine Locus FHM3

Alterations in the α2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2

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