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Dive into the research topics where Bente Vilsen is active.

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Featured researches published by Bente Vilsen.


Nature | 2007

Crystal structure of the sodium-potassium pump.

J. Preben Morth; Bjørn Panyella Pedersen; Mads S. Toustrup-Jensen; Thomas Lykke-Møller Sørensen; Janne Petersen; Jens Peter Andersen; Bente Vilsen; Poul Nissen

The Na+,K+-ATPase generates electrochemical gradients for sodium and potassium that are vital to animal cells, exchanging three sodium ions for two potassium ions across the plasma membrane during each cycle of ATP hydrolysis. Here we present the X-ray crystal structure at 3.5 Å resolution of the pig renal Na+,K+-ATPase with two rubidium ions bound (as potassium congeners) in an occluded state in the transmembrane part of the α-subunit. Several of the residues forming the cavity for rubidium/potassium occlusion in the Na+,K+-ATPase are homologous to those binding calcium in the Ca2+-ATPase of sarco(endo)plasmic reticulum. The β- and γ-subunits specific to the Na+,K+-ATPase are associated with transmembrane helices αM7/αM10 and αM9, respectively. The γ-subunit corresponds to a fragment of the V-type ATPase c subunit. The carboxy terminus of the α-subunit is contained within a pocket between transmembrane helices and seems to be a novel regulatory element controlling sodium affinity, possibly influenced by the membrane potential.


Nature Genetics | 2013

Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension

Felix Beuschlein; Sheerazed Boulkroun; Andrea Osswald; Thomas Wieland; Hang Nguyen Nielsen; Urs Lichtenauer; David Penton; Vivien Rodacker Schack; Laurence Amar; Evelyn Fischer; Anett Walther; Philipp Tauber; Thomas Schwarzmayr; Susanne Diener; Elisabeth Graf; Bruno Allolio; Benoit Samson-Couterie; Arndt Benecke; Marcus Quinkler; Francesco Fallo; Pierre-François Plouin; Franco Mantero; Thomas Meitinger; Paolo Mulatero; Xavier Jeunemaitre; Richard Warth; Bente Vilsen; Maria-Christina Zennaro; Tim M. Strom; Martin Reincke

Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na+/K+ ATPase α subunit) and ATP2B3 (encoding a Ca2+ ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutation-negative cases. In summary, dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion.


Nature Reviews Molecular Cell Biology | 2011

A structural overview of the plasma membrane Na+,K+-ATPase and H+-ATPase ion pumps

J. Preben Morth; Bjørn Panyella Pedersen; Morten J. Buch-Pedersen; Jens Peter Andersen; Bente Vilsen; Michael G. Palmgren; Poul Nissen

Plasma membrane ATPases are primary active transporters of cations that maintain steep concentration gradients. The ion gradients and membrane potentials derived from them form the basis for a range of essential cellular processes, in particular Na+-dependent and proton-dependent secondary transport systems that are responsible for uptake and extrusion of metabolites and other ions. The ion gradients are also both directly and indirectly used to control pH homeostasis and to regulate cell volume. The plasma membrane H+-ATPase maintains a proton gradient in plants and fungi and the Na+,K+-ATPase maintains a Na+ and K+ gradient in animal cells. Structural information provides insight into the function of these two distinct but related P-type pumps.


Nature | 2013

Crystal structure of a Na+-bound Na+,K+-ATPase preceding the E1P state

Ryuta Kanai; Haruo Ogawa; Bente Vilsen; Flemming Cornelius; Chikashi Toyoshima

Na+,K+-ATPase pumps three Na+ ions out of cells in exchange for two K+ taken up from the extracellular medium per ATP molecule hydrolysed, thereby establishing Na+ and K+ gradients across the membrane in all animal cells. These ion gradients are used in many fundamental processes, notably excitation of nerve cells. Here we describe 2.8 Å-resolution crystal structures of this ATPase from pig kidney with bound Na+, ADP and aluminium fluoride, a stable phosphate analogue, with and without oligomycin that promotes Na+ occlusion. These crystal structures represent a transition state preceding the phosphorylated intermediate (E1P) in which three Na+ ions are occluded. Details of the Na+-binding sites show how this ATPase functions as a Na+-specific pump, rejecting K+ and Ca2+, even though its affinity for Na+ is low (millimolar dissociation constant). A mechanism for sequential, cooperative Na+ binding can now be formulated in atomic detail.


FEBS Letters | 1995

Structure-function relationships of cation translocation by Ca2+- and Na+,K+-ATPases studied by site-directed mutagenesis

Jens Peter Anderssen; Bente Vilsen

Site‐directed mutagenesis studies of the sarcoplasmic reticulum Ca2+‐ATPase have pinpointed five amino acid residues that are essential to Ca2+ occlusion, and these residues have been assigned to different parts of a Ca2+ binding pocket with channel‐like structure. Three of the homologous Na+,K+‐ATPase residues have been shown to be important for binding of cytoplasmic Na+ at transport sites. In addition, three of the above mentioned Ca2+‐ATPase residues appear to participate in the countertransport of H+, and two of the Na+,K+‐ATPase residues to participate in the countertransport of K+. Residues involved in energy transducing conformational changes have also been identified by mutagenesis. In the Ca2+‐ATPase, ATP hydrolysis is uncoupled from Ca2+ transport following mutation of a tyrosine residue located at the top of transmembrane segment M5. This tyrosine, present also in the Na+,K+‐ATPase, may play a critical role in closing the gate to a transmembrane channel.


Lancet Neurology | 2014

Distinct neurological disorders with ATP1A3 mutations

Erin L. Heinzen; Alexis Arzimanoglou; Allison Brashear; Steven J. Clapcote; Fiorella Gurrieri; David B. Goldstein; Sigurður H Jóhannesson; Mohamad A. Mikati; Brian Neville; Sophie Nicole; Laurie J. Ozelius; Hanne Poulsen; Tsveta Schyns; Kathleen J. Sweadner; Arn M. J. M. van den Maagdenberg; Bente Vilsen

Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na(+)/K(+)-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in-vitro and animal model systems, and the role of Na(+)/K(+)-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases.


Proceedings of the National Academy of Sciences of the United States of America | 2009

Mutation I810N in the α3 isoform of Na+,K+-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

Steven J. Clapcote; Steven Duffy; Gang Xie; Greer S. Kirshenbaum; Allison R. Bechard; Vivien Rodacker Schack; Janne Petersen; Laleh Sinai; Bechara J. Saab; Jason P. Lerch; Berge A. Minassian; Cameron Ackerley; John G. Sled; Miguel A. Cortez; Jeffrey T. Henderson; Bente Vilsen; John C. Roder

In a mouse mutagenesis screen, we isolated a mutant, Myshkin (Myk), with autosomal dominant complex partial and secondarily generalized seizures, a greatly reduced threshold for hippocampal seizures in vitro, posttetanic hyperexcitability of the CA3-CA1 hippocampal pathway, and neuronal degeneration in the hippocampus. Positional cloning and functional analysis revealed that Myk/+ mice carry a mutation (I810N) which renders the normally expressed Na+,K+-ATPase α3 isoform inactive. Total Na+,K+-ATPase activity was reduced by 42% in Myk/+ brain. The epilepsy in Myk/+ mice and in vitro hyperexcitability could be prevented by delivery of additional copies of wild-type Na+,K+-ATPase α3 by transgenesis, which also rescued Na+,K+-ATPase activity. Our findings reveal the functional significance of the Na+,K+-ATPase α3 isoform in the control of epileptiform activity and seizure behavior.


Hypertension | 2014

Somatic ATP1A1, ATP2B3, and KCNJ5 Mutations in Aldosterone-Producing Adenomas

Tracy A. Williams; Silvia Monticone; Vivien Rodacker Schack; Julia Stindl; Jacopo Burrello; Fabrizio Buffolo; Laura Annaratone; Isabella Castellano; Felix Beuschlein; Martin Reincke; Barbara Lucatello; Vanessa Ronconi; Francesco Fallo; Giampaolo Bernini; Mauro Maccario; Gilberta Giacchetti; Franco Veglio; Richard Warth; Bente Vilsen; Paolo Mulatero

Aldosterone-producing adenomas (APAs) cause a sporadic form of primary aldosteronism and somatic mutations in the KCNJ5 gene, which encodes the G-protein–activated inward rectifier K+ channel 4, GIRK4, account for ≈40% of APAs. Additional somatic APA mutations were identified recently in 2 other genes, ATP1A1 and ATP2B3, encoding Na+/K+-ATPase 1 and Ca2+-ATPase 3, respectively, at a combined prevalence of 6.8%. We have screened 112 APAs for mutations in known hotspots for genetic alterations associated with primary aldosteronism. Somatic mutations in ATP1A1, ATP2B3, and KCNJ5 were present in 6.3%, 0.9%, and 39.3% of APAs, respectively, and included 2 novel mutations (Na+/K+-ATPase p.Gly99Arg and GIRK4 p.Trp126Arg). CYP11B2 gene expression was higher in APAs harboring ATP1A1 and ATP2B3 mutations compared with those without these or KCNJ5 mutations. Overexpression of Na+/K+-ATPase p.Gly99Arg and GIRK4 p.Trp126Arg in HAC15 adrenal cells resulted in upregulation of CYP11B2 gene expression and its transcriptional regulator NR4A2. Structural modeling of the Na+/K+-ATPase showed that the Gly99Arg substitution most likely interferes with the gateway to the ion binding pocket. In vitro functional assays demonstrated that Gly99Arg displays severely impaired ATPase activity, a reduced apparent affinity for Na+ activation of phosphorylation and K+ inhibition of phosphorylation that indicate decreased Na+ and K+ binding, respectively. Moreover, whole cell patch-clamp studies established that overexpression of Na+/K+-ATPase Gly99Arg causes membrane voltage depolarization. In conclusion, somatic mutations are common in APAs that result in an increase in CYP11B2 gene expression and may account for the dysregulated aldosterone production in a subset of patients with sporadic primary aldosteronism.


Proceedings of the National Academy of Sciences of the United States of America | 2011

Mania-like behavior induced by genetic dysfunction of the neuron-specific Na+,K+-ATPase α3 sodium pump.

Greer S. Kirshenbaum; Steven J. Clapcote; Steven Duffy; Christian R. Burgess; Janne Petersen; Karolina J. Jarowek; Yeni H. Yücel; Miguel A. Cortez; O. Carter Snead; Bente Vilsen; John H. Peever; Martin R. Ralph; John C. Roder

Bipolar disorder is a debilitating psychopathology with unknown etiology. Accumulating evidence suggests the possible involvement of Na+,K+-ATPase dysfunction in the pathophysiology of bipolar disorder. Here we show that Myshkin mice carrying an inactivating mutation in the neuron-specific Na+,K+-ATPase α3 subunit display a behavioral profile remarkably similar to bipolar patients in the manic state. Myshkin mice show increased Ca2+ signaling in cultured cortical neurons and phospho-activation of extracellular signal regulated kinase (ERK) and Akt in the hippocampus. The mood-stabilizing drugs lithium and valproic acid, specific ERK inhibitor SL327, rostafuroxin, and transgenic expression of a functional Na+,K+-ATPase α3 protein rescue the mania-like phenotype of Myshkin mice. These findings establish Myshkin mice as a unique model of mania, reveal an important role for Na+,K+-ATPase α3 in the control of mania-like behavior, and identify Na+,K+-ATPase α3, its physiological regulators and downstream signal transduction pathways as putative targets for the design of new antimanic therapies.


Philosophical Transactions of the Royal Society B | 2009

The structure of the Na+,K+-ATPase and mapping of isoform differences and disease-related mutations

J. Preben Morth; Hanne Poulsen; Mads S. Toustrup-Jensen; Vivien Rodacker Schack; Jan Egebjerg; Jens Peter Andersen; Bente Vilsen; Poul Nissen

The Na+,K+-ATPase transforms the energy of ATP to the maintenance of steep electrochemical gradients for sodium and potassium across the plasma membrane. This activity is tissue specific, in particular due to variations in the expressions of the alpha subunit isoforms one through four. Several mutations in alpha2 and 3 have been identified that link the specific function of the Na+,K+-ATPase to the pathophysiology of neurological diseases such as rapid-onset dystonia parkinsonism and familial hemiplegic migraine type 2. We show a mapping of the isoform differences and the disease-related mutations on the recently determined crystal structure of the pig renal Na+,K+-ATPase and a structural comparison to Ca2+-ATPase. Furthermore, we present new experimental data that address the role of a stretch of three conserved arginines near the C-terminus of the alpha subunit (Arg1003–Arg1005).

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