Migraine- and dystonia-related disease-mutations of Na+/K+-ATPases: Relevance of behavioral studies in mice to disease symptoms and neurological manifestations in humans

α3Na+/K+-ATPase Deficiency Causes Brain Ventricle Dilation and Abrupt Embryonic Motility in Zebrafish

“…Of particular relevance for this study is the fact that the water environment hosting zebrafish differs from other environments and thus requires other mechanisms for ion homeostasis to maintain osmolarity. However, we believe that it is not so extraordinary to observe a brain ventricle dilation phenotype in the Atp1a3 KD zebrafish, although this is not a manifestation observed in RDP patients harboring mutations in the ATP1A3 gene (47). Thus, we cannot rule out that the brain ventricle dilation is specific to zebrafish despite the conserved functions of the Na ϩ /K ϩ -ATPase.…”

Subunit Isoform Selectivity in Assembly of Na,K-ATPase α-β Heterodimers

“…Natural in vivo mutations in the ␣ 2 subunit are associated with familial hemiplegic migraine and epilepsy (16). Most of these mutations cause functional defects in active Na ϩ and K ϩ transport and impaired clearance of extracellular K ϩ or glutamate due to either the impairment of maturation and hence plasma membrane delivery of the enzyme, or the loss of the catalytic activity (16,53).…”

“…Most of these mutations cause functional defects in active Na ϩ and K ϩ transport and impaired clearance of extracellular K ϩ or glutamate due to either the impairment of maturation and hence plasma membrane delivery of the enzyme, or the loss of the catalytic activity (16,53). It is known that neurological diseases, particularly epilepsy, are closely associated with the ER stressrelated retention of essential ion transporters in the ER (54 -57).…”

“…The ␣ 2 isoform regulates contractility of cardiac, smooth, and skeletal muscle and plays a key role in the modulation of blood pressure in response to stress (3,14,15). In vivo human mutations in the ␣ 2 and ␣ 3 isoforms are associated with neurological diseases, familial hemiplegic migraine type 2, and rapid-onset dystonia-parkinsonism (16). The ␣ 4 isoform is required for sperm motility and fertility (10,11).…”

The α2Na+/K+-ATPase is critical for skeletal and heart muscle function in zebrafish

“…Mutations in the human ATP1A2 gene were reported to cause a rare inherited subtype of migraine with aura, Familial hemiplegic migraine type 2 (FHM2) (De Fusco et al, 2003), and since then, multiple mutations in the ATP1A2 gene have been linked to FHM2 (Bøttger et al, 2012). Astrocytic a 2 Na + /K + -ATPase plays an important role in clearance of K + from the extracellular space during neuronal activity (D' Ambrosio et al, 2002), and is fundamental also for the clearance of released glutamate from the synaptic cleft, because active reuptake of glutamate into astrocytes is driven by Na + and K + gradients (Cholet et al, 2002;Ikeda et al, 2004;Rose et al, 2009).…”