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J. Biol. Chem., Vol. 279, Issue 42, 43692-43696, October 15, 2004

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Kinetic Alterations due to a Missense Mutation in the Na,K-ATPase 2 Subunit Cause Familial Hemiplegic Migraine Type 2^*

Laura Segall, Rosemarie Scanzano, Mari A. Kaunisto, Maija Wessman, Aarno Palotie¶, J. Jay Gargus||, and Rhoda Blostein**

From the Departments of Biochemistry and Medicine, McGill University, Montreal, Quebec H3G 1A4, Canada, the ^||Department of Physiology and Biophysics and Section of Human Genetics, Department of Pediatrics, University of California, Irvine, California 92697-4034, Biomedicum Helsinki and the Department of Clinical Chemistry, University of Helsinki, Helsinki 00029 HUS, Finland, and ^¶The Finnish Genome Center, University of Helsinki, Helsinki 90095-7008, Finland, and the Departments of Pathology and Human Genetics, University of California, Los Angeles, California 90095-1361

A number of missense mutations in the ATP1A2 gene, which encodes the Na,K-ATPase 2 subunit, have been identified in familial hemiplegic migraine with aura. Loss of function and haploinsufficiency have been the suggested mechanisms in mutants for which functional analysis has been reported. This paper describes a kinetic analysis of mutant T345A, recently identified in a detailed genetic analysis of a large Finnish family (Kaunisto, M. A., Harno, H., Vanmolkot, K. R., Gargus, J. J., Sun, G., Hamalainen, E., Liukkonen, E., Kallela, M., van den Maagdenberg, A. M., Frants, R. R., Farkkila, M., Palotie, A., and Wessman, M. (2004) Neurogenetics 5, 141–146). Introducing T345A into the conserved rat 2 enzyme does not alter cell growth or catalytic turnover but causes a substantial decrease in apparent K⁺ affinity (2-fold increase in K_0.5(K+)). In view of the location of Thr-345 in the cytoplasmic stalk domain adjacent to transmembrane segment 4, the 2-fold increase in K_0.5(K+) is probably due to T345A replacement altering K⁺ occlusion/deocclusion. Faster K⁺ deocclusion of the mutant via the E₂(K) + ATP E₁·ATP + K⁺ partial reaction is evidenced in (i) a marked increase (300%) in K⁺ stimulation of Na-ATPase at micromolar ATP, (ii) a 4-fold decrease in K_ATP, and (iii) only a modest increase (3-fold) in I₅₀ for vanadate, which was used as a probe of the steady state E₁/E₂ conformational equilibrium. We suggest that the decreased apparent K⁺ affinity is the basis for a reduced rate of extracellular K⁺ removal, which delays the recovery phase of nerve impulse transmission in the central nervous system and, thereby, the clinical picture of migraine with aura. This is the first demonstration of a mutation that leads to a disease associated with a kinetically altered but fully functional Na,K-ATPase, refining the molecular mechanism of pathogenesis in familial hemiplegic migraine.

Received for publication, July 6, 2004 , and in revised form, August 2, 2004.

^* This work was supported by Grant MT-3876 from the Canadian Institutes of Health Research (to R. B.), Grants MH59222 (to J. J. G.) and NS37675-02 (to A. P.) from the National Institutes of Health, and by The Research Funds of the Helsinki University Central Hospital, The Research Foundation of the University of Helsinki, The Juselius Foundation, the Academy of Finland, and a Young Scientist's Award (to M. A. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Montreal General Hospital Research Institute, 1650 Cedar Ave., Montreal, Quebec H3G 1A4, Canada. Tel.: 514-934-1934 (ext. 44501); Fax: 514-934-8332; E-mail: Rhoda.Blostein{at}mcgill.ca.

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