Genetic effects of ATP1A2 in familial hemiplegic migraine type II and animal models

Stephanie M Gritz,Richard A Radcliffe

doi:10.1186/1479-7364-7-8

Abstract

Na+/K+-ATPase alpha 2 (Atp1a2) is an integral plasma membrane protein belonging to the P-type ATPase family that is responsible for maintaining the sodium (Na+) and potassium (K+) gradients across cellular membranes with hydrolysis of ATP. Atp1a2 contains two subunits, alpha and beta, with each having various isoforms and differential tissue distribution. In humans, mutations in ATP1A2 are associated with a rare form of hereditary migraines with aura known as familial hemiplegic migraine type II. Genetic studies in mice have revealed other neurological effects of Atp1a2 in mice including anxiety, fear, and learning and motor function disorders. This paper reviews the recent findings in the literature concerning Atp1a2.

Highlights

The integral plasma membrane protein Na+/K+-ATPase is a member of the P-type ATPase family
Mutations and deficiencies in Na+/K+-ATPase α2 (Atp1a2) are associated with familial hemiplegic migraine type II (FHM2) in patients suffering from migraines with hemiplegia and partial paralysis during the aura phase
FHM2 patients may have increased susceptibility to cortical spreading depression (CSD), which may be due to the increase in extracellular potassium and/or a decrease in glutamate clearance

Summary

Introduction

The integral plasma membrane protein Na+/K+-ATPase is a member of the P-type ATPase family. The T2763C mutation causes the amino acid substitution W887R, which affects the β subunit binding site in Atp1a2, resulting in a misfolding of the protein and, in cell-based studies, a complete loss of pump function. The knock-in mice were tested for CSD by electrical stimulation, and results showed that they were more susceptible to CSD: they had a higher threshold and velocity but equal duration of CSD than the wild type These results may be due to the impaired clearance of extracellular potassium and glutamate by astrocytes, which is comparable to the effects of FHM2 mutations in humans [23,26]. Further testing on this mouse model will be beneficial to understanding the mechanism of at least this mutation in FHM and possible treatment avenues

Conclusions

Kaplan JH

Findings

23. Pietrobon D