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Mads Schak Toustrup-Jensen

Relationship between intracellular Na+ concentration and reduced Na+ affinity in Na+,K+-ATPase mutants causing neurological disease

Publikation: KonferencebidragPosterForskning

The neurological disorders familial hemiplegic migraine type 2 (FHM2), alternating hemiplegia of childhood (AHC), and rapid-onset dystonia parkinsonism (RDP) are caused by mutations of Na+,K+-ATPase α2 and α3 isoforms, expressed in glial and neuronal cells, respectively. Although these disorders are distinct, they overlap in phenotypical presentation. Two Na+,K+-ATPase mutations, extending the C terminus by either 28 residues ("+28" mutation) or an extra tyrosine ("+Y"), are associated with FHM2 and RDP, respectively. We describe here functional consequences of these and other neurological disease mutations as well as an extension of the C terminus only by a single alanine. The dependence of the mutational effects on the specific α isoform in which the mutation is introduced was furthermore studied. At the cellular level we have characterized the C-terminal extension mutants and other mutants, addressing the question to what extent they cause a change of the intracellular Na+ and K+ concentrations ([Na+]i and [K+]i) in COS cells. C-terminal extension mutants generally showed dramatically reduced Na+ affinity without disturbance of K+ binding, as did other RDP mutants. No phosphorylation from ATP was observed for the +28 mutation of α2 despite a high expression level. A significant rise of [Na+]i and reduction of [K+]i was detected in cells expressing mutants with reduced Na+ affinity and did not require a concomitant reduction of the maximal catalytic turnover rate or expression level. Moreover, two mutations that increase Na+ affinity were found to reduce [Na+]i. It is concluded that the Na+ affinity of the Na+,K+-ATPase is an important determinant of [Na+]i.
OriginalsprogEngelsk
Udgivelsesår30 aug. 2014
StatusUdgivet - 30 aug. 2014
Begivenhed14th International ATPase Conference “Na,K‐ATPase and related transport ATPases: Structure, mechanism, cell biology, health and disease” - Conference Center De Werelt, Lunteren, Holland
Varighed: 30 aug. 20145 sep. 2014

Konference

Konference14th International ATPase Conference “Na,K‐ATPase and related transport ATPases: Structure, mechanism, cell biology, health and disease”
LokationConference Center De Werelt
LandHolland
ByLunteren
Periode30/08/201405/09/2014

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