Diverse Functional Consequences of Mutations in the Na+/K+-ATPase α2-Subunit Causing Familial Hemiplegic Migraine Type 2

Mutations in ATP1A2, the gene coding for the Na+/K+-ATPase α2-subunit, are associated with both familial hemiplegic migraine and sporadic cases of hemiplegic migraine. In this study, we examined the functional properties of 11 ATP1A2 mutations associated with familial or sporadic hemiplegic migraine...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2008-11, Vol.283 (45), p.31097-31106
Main Authors: Tavraz, Neslihan N., Friedrich, Thomas, Dürr, Katharina L., Koenderink, Jan B., Bamberg, Ernst, Freilinger, Tobias, Dichgans, Martin
Format: Article
Language:English
Subjects:
Membrane Transport, Structure, Function, and Biogenesis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Mutations in ATP1A2, the gene coding for the Na+/K+-ATPase α2-subunit, are associated with both familial hemiplegic migraine and sporadic cases of hemiplegic migraine. In this study, we examined the functional properties of 11 ATP1A2 mutations associated with familial or sporadic hemiplegic migraine, including missense mutations (T263M, T376M, R383H, A606T, R763H, M829R, R834Q, R937P, and X1021R), a deletion mutant (del(K935-S940)ins(I)), and a frameshift mutation (S966fs). According to the Na+/K+-ATPase crystal structure, a subset of the mutated residues (Ala606, Arg763, Met829, and Arg834) is involved in important interdomain H-bond networks, and the C terminus of the enzyme, which is elongated by the X1021R mutation, has been implicated in voltage dependence and formation of a third Na+-binding site. Upon heterologous expression in Xenopus oocytes, the analysis of electrogenic transport properties, Rb+ uptake, and protein expression revealed pronounced and markedly diverse functional alterations in all ATP1A2 mutants. Abnormalities included a complete loss of function (T376M), impaired plasma membrane expression (del(K935-S940)ins(I) and S966fs), and altered apparent affinities for extracellular cations or reduced enzyme turnover (R383H, A606T, R763H, R834Q, and X1021R). In addition, changes in the voltage dependence of pump currents and the increased rate constants of the voltage jump-induced redistribution between E1P and E2P states were observed. Thus, mutations that disrupt distinct interdomain H-bond patterns can cause abnormal conformational flexibility and exert long range consequences on apparent cation affinities or voltage dependence. Of interest, the X1021R mutation severely impaired voltage dependence and kinetics of Na+-translocating partial reactions, corroborating the critical role of the C terminus of Na+/K+-ATPase in these processes.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M802771200