The ATP1A2 gene is located on chromosome 1q23 and encodes the α2-subunit of the Na+/K+-ATPase. This protein is a plasma membrane enzyme that plays a critical role in the normal function of neurons. Within the central nervous system α2-subunit of the Na+/K+-ATPase is primarily expressed in astrocytes. The sodium-potassium pump is responsible for the control of extracellular K+ concentration and Na+-gradient. It creates a steep sodium gradient, by exchanging intracellular Na+ ions for extracellular K+ ions. Hereby the pump directly facilitates the removal of extracellular K+ ions and indirectly facilitates the removal of glutamate from the synaptic cleft into glial cells.
Clear genotype-phenotype correlations in FHM2/SHM2 in patients are almost impossible to make. Therefore, cellular models and animal models offer a solution for better understanding the spectrum and molecular mechanisms behind FHM2/SHM2. Cellular models show that mutations in ATP1A2 causing FHM2/SHM2 are not merely the result of a loss-of-function, but can show a more complex mechanism by changing the K+-gradient and Na+-gradient. Thus far, three ATP1A2 knock-out and two ATP1A2 knock-in mice have been described. Only heterozygous mouse models have proven to be viable. These mice show increased fear and anxiety behaviour, which might be correlated to the abnormal function of the amygdala and piriform cortex also seen in these animals. Furthermore, the models show a dysfunction in the removal of glutamate and GABA from the synaptic cleft.
Taken together it is predicted that mutations in ATP1A2 lead to dysfunctional uptake of K+ ions and glutamate from the synaptic cleft. It is hypothesized that these altered levels of K+ ions and glutamate in the synaptic cleft renders neurons unbalanced, this leaves them vulnerable and thus might facilitate cortical spreading depression (CSD). CSD is a possible mechanism in the development of aura in migraine.
Almost all mutations in the ATPA2 gene causing familial/sporadic hemiplegic migraine type 2 are amino acid changes, although small deletions have been found.