Na,K-ATPase mutations in familial hemiplegic migraine lead to functional inactivation |
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Authors: | Jan B Koenderink Li Yan Qiu Jan Joep HHM De Pont Thomas Friedrich |
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Institution: | a Department of Biochemistry, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500HB Nijmegen, The Netherlands b Max-Planck-Institute of Biophysics, Department of Biophysical Chemistry, Max-von-Laue-Str. 3, D-60438 Frankfurt am Main, Germany c Johann-Wolfgang-Goethe-University Frankfurt am Main, Department of Chemical and Pharmaceutical Sciences, Marie-Curie-Str. 9, D-60439 Frankfurt am Main, Germany |
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Abstract: | The Na,K-ATPase is an ion-translocating transmembrane protein that actively maintains the electrochemical gradients for Na+ and K+ across the plasma membrane. The functional protein is a heterodimer comprising a catalytic α-subunit (four isoforms) and an ancillary β-subunit (three isoforms). Mutations in the α2-subunit have recently been implicated in familial hemiplegic migraine type 2, but almost no thorough studies of the functional consequences of these mutations have been provided. We investigated the functional properties of the mutations L764P and W887R in the human Na,K-ATPase α2-subunit upon heterologous expression in Xenopus oocytes. No Na,K-ATPase-specific pump currents could be detected in cells expressing these mutants. The binding of radiolabelled 3H]ouabain to intact cells suggested that this could be due to a lack of plasma membrane expression. However, plasma membrane isolation showed that the mutated pumps are well expressed at the plasma membrane. 86Rb+-flux and ATPase activity measurements demonstrated that the mutants are inactive. Therefore, the primary disease-causing mechanism is loss-of-function of the Na,K-ATPase α2-isoform. |
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Keywords: | Human Na+/K+-ATPase α2-subunit ATP1A2 Familial hemiplegic migraine type 2 Pump current Surface expression ATP hydrolysis |
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