Functional effects of Na+,K+-ATPase gene mutations linked to familial hemiplegic migraine

Familial hemiplegic migraine type 2, an autosomal dominant form of migraine with aura, has been associated with four distinct mutations in the alpha 2-subunit of the Na+,K+-ATPase. We have introduced these mutations in the alpha 2-subunit of the human Na+,K+-ATPase and the corresponding mutations in the Bufo marinus alpha 1-subunit and studied these mutants by expression in Xenopus oocyte. Metabolic labeling studies showed that the mutants were synthesized and associated with the beta-subunit, except for the alpha 2(H)W887R mutant, which was poorly synthesized, and the alpha 1(B)W890R, which was partially retained in the endoplasmic reticulum. [H-3]ouabain binding showed the presence of the alpha 2(H)R689Q and alpha 2(H)M731T at the membrane, whereas the alpha 2(H)L764P and alpha 2(H)W887R could not be detected. Functional studies with the mutants of the B. marinus Na+,K-ATPase showed a reduced or abolished electrogenic activity and a low K+ affinity for the alpha 1(B)890R mutant. Through different mechanisms, all these mutations result in a strong decrease of the functional expression of the Na+,K+-pump. The decreased activity in alpha 2 isoform of the Na+,K+-pump expressed in astrocytes seems an essential component of hemiplegic migraine pathogenesis and may be responsible for the cortical spreading depression, which is one of the first events in migraine attacks.