Na⁺, K⁺-ATPase

The adenosine triphosphatases (ATPases) are integral membrane proteins that actively exchange ions across cell membranes; the energy required for this process is derived from hydrolysis of one molecule of ATP. The sodium (Na⁺), potassium (K⁺) ATPase (Na⁺, K⁺-ATPase) simultaneously extrudes 3 Na⁺ ions from the intracellular compartment in exchange for 2 K⁺ ions from the extracellular space. The Na⁺, K⁺-ATPase maintains the Na⁺ and K⁺ gradients that are of fundamental importance for maintenance of neuronal excitability and conduction of the action potential and for secondary transport systems involved in synaptic uptake of neurotransmitters and regulation of cell volume, pH, and calcium (Ca²⁺) concentrations. The Na⁺, K⁺-ATPase forms macromolecular complexes with other membrane proteins and triggers intracellular transduction signals involved in synaptic plasticity. There are different isoforms of the Na⁺, K⁺-ATPase expressed in neurons and glial cells. Impaired Na⁺, K⁺-ATPase activity, resulting from reduced ATP availability due to mitochondrial dysfunction in the setting of hypoxia, ischemia, inflammation, and other conditions, triggers neuronal depolarization, cytotoxic edema, and neuronal, axonal, and glial injury. The elucidation of the cristal structure of the catalytic α subunit of the Na⁺, K⁺-ATPase and the functional consequences of specific mutations have led to identification of specific amino acid sequences that are critical for the normal function of the enzyme. Mutations affecting the α2 subunit of the Na⁺, K⁺-ATPase, which is expressed in astrocytes, is linked to familial hemiplegic migraine type 2 (FHM2); mutations affecting the α3 subunit, which is expressed in neurons, are linked to rapid onset dystonia and parkinsonism. The structure and function of the Na⁺, K⁺-ATPase and …