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J Biol Chem
2008 Nov 07;28345:31097-106. doi: 10.1074/jbc.M802771200.
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Diverse functional consequences of mutations in the Na+/K+-ATPase alpha2-subunit causing familial hemiplegic migraine type 2.
Tavraz NN
,
Friedrich T
,
Dürr KL
,
Koenderink JB
,
Bamberg E
,
Freilinger T
,
Dichgans M
.
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Mutations in ATP1A2, the gene coding for the Na(+)/K(+)-ATPase alpha(2)-subunit, are associated with both familial hemiplegic migraine and sporadic cases of hemiplegic migraine. In this study, we examined the functional properties of 11 ATP1A2 mutations associated with familial or sporadic hemiplegic migraine, including missense mutations (T263M, T376M, R383H, A606T, R763H, M829R, R834Q, R937P, and X1021R), a deletion mutant (del(K935-S940)ins(I)), and a frameshift mutation (S966fs). According to the Na(+)/K(+)-ATPase crystal structure, a subset of the mutated residues (Ala(606), Arg(763), Met(829), and Arg(834)) is involved in important interdomain H-bond networks, and the C terminus of the enzyme, which is elongated by the X1021R mutation, has been implicated in voltage dependence and formation of a third Na(+)-binding site. Upon heterologous expression in Xenopus oocytes, the analysis of electrogenic transport properties, Rb(+) uptake, and protein expression revealed pronounced and markedly diverse functional alterations in all ATP1A2 mutants. Abnormalities included a complete loss of function (T376M), impaired plasma membrane expression (del(K935-S940)ins(I) and S966fs), and altered apparent affinities for extracellular cations or reduced enzyme turnover (R383H, A606T, R763H, R834Q, and X1021R). In addition, changes in the voltage dependence of pump currents and the increased rate constants of the voltage jump-induced redistribution between E(1)P and E(2)P states were observed. Thus, mutations that disrupt distinct interdomain H-bond patterns can cause abnormal conformational flexibility and exert long range consequences on apparent cation affinities or voltage dependence. Of interest, the X1021R mutation severely impaired voltage dependence and kinetics of Na(+)-translocating partial reactions, corroborating the critical role of the C terminus of Na(+)/K(+)-ATPase in these processes.
Albers,
Biochemical aspects of active transport.
1967, Pubmed
Albers,
Biochemical aspects of active transport.
1967,
Pubmed
Axelsen,
Evolution of substrate specificities in the P-type ATPase superfamily.
1998,
Pubmed
De Fusco,
Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2.
2003,
Pubmed
Dichgans,
Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine.
,
Pubmed
Ducros,
The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel.
2001,
Pubmed
Golovina,
Na+ pump alpha 2-subunit expression modulates Ca2+ signaling.
2003,
Pubmed
Hadjikhani,
Mechanisms of migraine aura revealed by functional MRI in human visual cortex.
2001,
Pubmed
Jorgensen,
Structure and mechanism of Na,K-ATPase: functional sites and their interactions.
2003,
Pubmed
Jorgensen,
Role of conserved TGDGVND-loop in Mg2+ binding, phosphorylation, and energy transfer in Na,K-ATPase.
2001,
Pubmed
Jurkat-Rott,
Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase variants.
2004,
Pubmed
Kamsteeg,
Detection of aquaporin-2 in the plasma membranes of oocytes: a novel isolation method with improved yield and purity.
2001,
Pubmed
,
Xenbase
Kaplan,
Biochemistry of Na,K-ATPase.
2002,
Pubmed
Kaunisto,
A novel missense ATP1A2 mutation in a Finnish family with familial hemiplegic migraine type 2.
2004,
Pubmed
Koenderink,
Electrophysiological analysis of the mutated Na,K-ATPase cation binding pocket.
2003,
Pubmed
,
Xenbase
Koenderink,
Na,K-ATPase mutations in familial hemiplegic migraine lead to functional inactivation.
2005,
Pubmed
,
Xenbase
McGrail,
Immunofluorescent localization of three Na,K-ATPase isozymes in the rat central nervous system: both neurons and glia can express more than one Na,K-ATPase.
1991,
Pubmed
Morth,
Crystal structure of the sodium-potassium pump.
2007,
Pubmed
Moseley,
The Na,K-ATPase alpha 2 isoform is expressed in neurons, and its absence disrupts neuronal activity in newborn mice.
2003,
Pubmed
Moskowitz,
Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes.
2004,
Pubmed
Nakao,
Voltage dependence of Na translocation by the Na/K pump.
,
Pubmed
Ogawa,
Homology modeling of the cation binding sites of Na+K+-ATPase.
2002,
Pubmed
Ophoff,
Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.
1996,
Pubmed
Orlowski,
Tissue-specific and developmental regulation of rat Na,K-ATPase catalytic alpha isoform and beta subunit mRNAs.
1988,
Pubmed
Peng,
Isoforms of Na,K-ATPase alpha and beta subunits in the rat cerebellum and in granule cell cultures.
1997,
Pubmed
Pierelli,
A novel ATP1A2 mutation in a family with FHM type II.
2006,
Pubmed
Pietrobon,
Neurobiology of migraine.
2003,
Pubmed
Post,
Activation by adenosine triphosphate in the phosphorylation kinetics of sodium and potassium ion transport adenosine triphosphatase.
1972,
Pubmed
Price,
Structure-function relationships in the Na,K-ATPase alpha subunit: site-directed mutagenesis of glutamine-111 to arginine and asparagine-122 to aspartic acid generates a ouabain-resistant enzyme.
1988,
Pubmed
Rakowski,
A negative slope in the current-voltage relationship of the Na+/K+ pump in Xenopus oocytes produced by reduction of external [K+].
1991,
Pubmed
,
Xenbase
Riant,
ATP1A2 mutations in 11 families with familial hemiplegic migraine.
2005,
Pubmed
Segall,
Alterations in the alpha2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2.
2005,
Pubmed
Segall,
Kinetic alterations due to a missense mutation in the Na,K-ATPase alpha2 subunit cause familial hemiplegic migraine type 2.
2004,
Pubmed
Somjen,
Mechanisms of spreading depression and hypoxic spreading depression-like depolarization.
2001,
Pubmed
Spadaro,
A G301R Na+/K+ -ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs.
2004,
Pubmed
Swoboda,
Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation.
2004,
Pubmed
Thomsen,
The genetic spectrum of a population-based sample of familial hemiplegic migraine.
2007,
Pubmed
Todt,
Rare missense variants in ATP1A2 in families with clustering of common forms of migraine.
2005,
Pubmed
,
Xenbase
Tonelli,
Amino acid changes in the amino terminus of the Na,K-adenosine triphosphatase alpha-2 subunit associated to familial and sporadic hemiplegic migraine.
2007,
Pubmed
Toyoshima,
Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 A resolution.
2000,
Pubmed
Toyoshima,
Structural changes in the calcium pump accompanying the dissociation of calcium.
2002,
Pubmed
Vanmolkot,
Severe episodic neurological deficits and permanent mental retardation in a child with a novel FHM2 ATP1A2 mutation.
2006,
Pubmed
Vanmolkot,
New discoveries about the second gene for familial hemiplegic migraine, ATP1A2.
2003,
Pubmed
Vanmolkot,
The novel p.L1649Q mutation in the SCN1A epilepsy gene is associated with familial hemiplegic migraine: genetic and functional studies. Mutation in brief #957. Online.
2007,
Pubmed
Vanmolkot,
Two de novo mutations in the Na,K-ATPase gene ATP1A2 associated with pure familial hemiplegic migraine.
2006,
Pubmed
Vanmolkot,
Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions.
2003,
Pubmed
Watts,
Cell-specific expression of mRNAs encoding Na+,K(+)-ATPase alpha- and beta-subunit isoforms within the rat central nervous system.
1991,
Pubmed
