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J Biol Chem
2019 Jan 04;2941:269-280. doi: 10.1074/jbc.RA118.004591.
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Functional consequences of the CAPOS mutation E818K of Na+,K+-ATPase.
Roenn CP
,
Li M
,
Schack VR
,
Forster IC
,
Holm R
,
Toustrup-Jensen MS
,
Andersen JP
,
Petrou S
,
Vilsen B
.
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The cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome is caused by the single mutation E818K of the α3-isoform of Na+,K+-ATPase. Here, using biochemical and electrophysiological approaches, we examined the functional characteristics of E818K, as well as of E818Q and E818A mutants. We found that these amino acid substitutions reduce the apparent Na+ affinity at the cytoplasmic-facing sites of the pump protein and that this effect is more pronounced for the lysine and glutamine substitutions (3-4-fold) than for the alanine substitution. The electrophysiological measurements indicated a more conspicuous, ∼30-fold reduction of apparent Na+ affinity for the extracellular-facing sites in the CAPOS mutant, which was related to an accelerated transition between the phosphoenzyme intermediates E1P and E2P. The apparent affinity for K+ activation of the ATPase activity was unaffected by these substitutions, suggesting that primarily the Na+-specific site III is affected. Furthermore, the apparent affinities for ATP and vanadate were WT-like in E818K, indicating a normal E1-E2 equilibrium of the dephosphoenzyme. Proton-leak currents were not increased in E818K. However, the CAPOS mutation caused a weaker voltage dependence of the pumping rate and a stronger inhibition by cytoplasmic K+ than the WT enzyme, which together with the reduced Na+ affinity of the cytoplasmic-facing sites precluded proper pump activation under physiological conditions. The functional deficiencies could be traced to the participation of Glu-818 in an intricate hydrogen-bonding/salt-bridge network, connecting it to key residues involved in Na+ interaction at site III.
Azizan,
Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension.
2013, Pubmed
Azizan,
Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension.
2013,
Pubmed
Baginski,
Microdetermination of inorganic phosphate, phospholipids, and total phosphate in biologic materials.
1967,
Pubmed
Blanco,
Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function.
1998,
Pubmed
Chang,
Novel pregnancy-triggered episodes of CAPOS syndrome.
2018,
Pubmed
Cornelius,
Metal fluoride complexes of Na,K-ATPase: characterization of fluoride-stabilized phosphoenzyme analogues and their interaction with cardiotonic steroids.
2011,
Pubmed
Dard,
Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation.
2015,
Pubmed
De Fusco,
Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2.
2003,
Pubmed
Demos,
A novel recurrent mutation in ATP1A3 causes CAPOS syndrome.
2014,
Pubmed
Duat Rodriguez,
Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
2017,
Pubmed
Han,
ATP1A3 mutations can cause progressive auditory neuropathy: a new gene of auditory synaptopathy.
2017,
Pubmed
Hayashida,
Further characterization of CAPOS/CAOS syndrome with the Glu818Lys mutation in the ATP1A3 gene: A case report.
2018,
Pubmed
Heimer,
CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene.
2015,
Pubmed
Heinzen,
De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.
2012,
Pubmed
Holm,
Neurological disease mutations of α3 Na+,K+-ATPase: Structural and functional perspectives and rescue of compromised function.
2016,
Pubmed
Holm,
Rescue of Na+ affinity in aspartate 928 mutants of Na+,K+-ATPase by secondary mutation of glutamate 314.
2015,
Pubmed
Kanai,
Crystal structure of a Na+-bound Na+,K+-ATPase preceding the E1P state.
2013,
Pubmed
Kaneko,
Ionic leakage underlies a gain-of-function effect of dominant disease mutations affecting diverse P-type ATPases.
2014,
Pubmed
Kaplan,
Biochemistry of Na,K-ATPase.
2002,
Pubmed
Li,
A functional correlate of severity in alternating hemiplegia of childhood.
2015,
Pubmed
,
Xenbase
Li,
A third Na+-binding site in the sodium pump.
2005,
Pubmed
,
Xenbase
Maas,
The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene.
2016,
Pubmed
McLean,
Distribution of the Na,K-ATPase alpha subunit in the rat spiral ganglion and organ of corti.
2009,
Pubmed
Meier,
Hyperpolarization-activated inward leakage currents caused by deletion or mutation of carboxy-terminal tyrosines of the Na+/K+-ATPase {alpha} subunit.
2010,
Pubmed
,
Xenbase
Meyer,
On the effect of hyperaldosteronism-inducing mutations in Na/K pumps.
2017,
Pubmed
,
Xenbase
Mitchell,
Sodium and proton effects on inward proton transport through Na/K pumps.
2014,
Pubmed
,
Xenbase
Morth,
Crystal structure of the sodium-potassium pump.
2007,
Pubmed
Nakao,
Voltage dependence of Na translocation by the Na/K pump.
,
Pubmed
Nicolaides,
Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS): a new syndrome.
1996,
Pubmed
Paciorkowski,
Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly.
2015,
Pubmed
Panagiotakaki,
Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.
2015,
Pubmed
Petrou,
P2X7 purinoceptor expression in Xenopus oocytes is not sufficient to produce a pore-forming P2Z-like phenotype.
1997,
Pubmed
,
Xenbase
Poulsen,
Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPase.
2010,
Pubmed
,
Xenbase
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,
Charge movement by the Na/K pump in Xenopus oocytes.
1993,
Pubmed
,
Xenbase
Rosewich,
Phenotypic overlap of alternating hemiplegia of childhood and CAPOS syndrome.
2014,
Pubmed
Rosewich,
Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study.
2012,
Pubmed
SKOU,
The influence of some cations on an adenosine triphosphatase from peripheral nerves.
1957,
Pubmed
Sagar,
Access channel model for the voltage dependence of the forward-running Na+/K+ pump.
1994,
Pubmed
,
Xenbase
Shull,
Molecular cloning of three distinct forms of the Na+,K+-ATPase alpha-subunit from rat brain.
1986,
Pubmed
Toustrup-Jensen,
Relationship between intracellular Na+ concentration and reduced Na+ affinity in Na+,K+-ATPase mutants causing neurological disease.
2014,
Pubmed
Toustrup-Jensen,
The C terminus of Na+,K+-ATPase controls Na+ affinity on both sides of the membrane through Arg935.
2009,
Pubmed
Toustrup-Jensen,
Importance of Glu(282) in transmembrane segment M3 of the Na(+),K(+)-ATPase for control of cation interaction and conformational changes.
2002,
Pubmed
Tranebjærg,
The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.
2018,
Pubmed
Vedovato,
Route, mechanism, and implications of proton import during Na+/K+ exchange by native Na+/K+-ATPase pumps.
2014,
Pubmed
,
Xenbase
Vilsen,
Leucine 332 at the boundary between the fourth transmembrane segment and the cytoplasmic domain of Na+,K+-ATPase plays a pivotal role in the ion translocating conformational changes.
1997,
Pubmed
Vilsen,
Functional consequences of alterations to Pro328 and Leu332 located in the 4th transmembrane segment of the alpha-subunit of the rat kidney Na+,K(+)-ATPase.
1992,
Pubmed
Wang,
A conformation of Na(+)-K+ pump is permeable to proton.
1995,
Pubmed
,
Xenbase
Yaragatupalli,
Altered Na+ transport after an intracellular alpha-subunit deletion reveals strict external sequential release of Na+ from the Na/K pump.
2009,
Pubmed
,
Xenbase
de Carvalho Aguiar,
Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism.
2004,
Pubmed
