Impaired plasma membrane targeting or protein stability by certain ATP1A2 mutations identified in sporadic or familial hemiplegic migraine.

Mutations in three different genes have been implicated in familial hemiplegic migraine (FHM), two of them code for neuronal voltage-gated cation channels, CACNA1A and SCN1A, while the third encodes ATP1A2, the α 2-isoform of the Na+/K+-ATPase's catalytic subunit, thus classifying FHM as an ion channel / ion transporter disorder. The Na+/K+-ATPase maintains the physiological gradients for Na+ and K+ ions and is therefore critical for the activity of ion channels and transporters involved in neurotransmitter uptake or Ca2+ signaling. Diverse functional abnormalities have been identified for disease-linked ATP1A2 mutations, which reach far beyond simple loss-of-function. We have shown recently that ATP1A2 mutations frequently lead to changes in the enzyme's voltage-dependent properties, kinetics, or apparent cation affinities. Here, we present functional data on a so far uncharacterized set of ATP1A2 mutations (G301R, R908Q, and P979L) upon expression in Xenopus oocytes and HEK293FT cells, and provide evide...