NaKATPases

NaKATPases, also known as Na+/K+-ATPases, are P-type ATPases that use ATP hydrolysis to actively transport Na+ and K+ across the plasma membrane. In each transport cycle the pump extrudes three Na+ ions from the cytoplasm and imports two K+ ions, establishing concentration gradients essential for membrane potential, cell volume regulation, and secondary active transport. They are ubiquitous in animal cells, with high expression in neurons, cardiac muscle, and kidney epithelia.

The functional pump is a heteromeric complex, typically comprising a catalytic α subunit and a glycosylated β subunit; vertebrates also express regulatory subunits of the FXYD family that modify affinity and turnover. The α subunit contains the catalytic and ion-binding sites and is the target of cardiac glycosides such as ouabain and digoxin.

Mechanistically, NaKATPases operate through an E1–E2 conformational cycle. In E1, the pump binds three intracellular Na+. ATP-dependent phosphorylation creates an E1P intermediate, driving a transition to E2P and release of Na+ on the extracellular side. Two extracellular K+ ions bind, the pump is dephosphorylated, and the return to E1 releases K+ inside. The reaction is electrogenic, contributing to the resting membrane potential.

Beyond transport, NaKATPases participate in signaling, with cardiac glycoside binding triggering cascades involving Src and MAP kinases in some cell types. Clinically, inhibition of the pump by glycosides increases intracellular Na+ and Ca2+ via the Na+/Ca2+ exchanger, providing inotropic support in heart failure. Mutations in Na+/K+-ATPase subunits are linked to neurological disorders such as rapid-onset dystonia parkinsonism and familial hemiplegic migraine.