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Mechanism of cation translocation by the Na, K-ATPase and related P-ATPases

Applicant Horisberger Jean-Daniel
Number 65441
Funding scheme Project funding
Research institution Département de Pharmacologie & Toxicologie Faculté de Biologie et de Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Physiology : other topics
Start/End 01.10.2001 - 30.09.2006
Approved amount 708'333.00
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Keywords (11)

PROTEIN 3-D STRUCTURE; SITE DIRECTED MUTAGENESIS; PALYTOXIN; STRUCTURE-FUNCTION RE-; LATIONSHIP; CYSTEINE ACCESSIBILITY; CATION TRANSPORT; CATION BINDING SITE; NA; K-ATP ASE; H

Lay Summary (English)

Lead
Lay summary
The Na,K-ATPase is responsible for the maintenance of Na and K gradients across the membrane of all animal cells. It is also one of the best studied P-type ATPase. Our experimental studies using functional exploration of mutations in the extracellular domain of Na,K-ATPase alpha subunit ATPase have allowed to demonstrate the role of the second and third extracellular loop in the "gate" that controls the access of extracellular K ions to their binding site. We have also identified the binding site for the 3rd Na ion that was only conjectural until now.Mutations around this site produce large changes in the kinetic of the electrogenic release of Na from its occlusion site and provide a new insight into the way cations are transported by the Na,K-pump. In addition we have shown that a proton flux that can be observed through Na,K-ATPase in the absence of extracelular Na and K ions follows the same pathway as the third Na ion.We have explored the effects of four of missense mutations found in the gene of the alpha2 subunit of the Na,K-ATPase, mutations which are associated with a hereditary form of migraine. We observed that all these mutations result in a reduced transport function of the Na,K-pump, but for different reasons: poor cell surface expression, poor association with the beta subunit, low affinity for extracellular K or functionally dead mutants. The migraine phenotype can thus probably be attributed to a reduced transport function of the Na,K-pump in the glial cells, the main site of the alpha2 isoform in the adult brain.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
113576 Molecular mechanism and regulation of potassium transport 01.10.2006 Project funding
45867 Structure-function relationship of the Na,K-ATPase: Mechanism of cation translocation 01.04.1996 Project funding

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