The Na+, K+-ATPase resides in the plasma membrane and actively transports three Na+ ions out and two K+ ions in per ATP. This maintains the membrane potential, enabling nerve impulses and osmotic balance. Using giant crab nerve, Skou showed for the first time that an ATPase activity and ion exchange are properties of the same protein. The finding became textbook physiology and guided development of drugs such as digitalis for heart failure.

Na+, K+-ATPase belongs to the P-type ATPase family and operates via an E1→E1~P→E2-P→E2 cycle involving phosphorylation of an aspartate residue. X-ray and cryo-EM structures revealed that ion-binding sites face alternately opposite membrane surfaces—an “alternating access” mechanism. Consuming roughly one-third of cellular ATP, the pump is vital for neuronal excitability, renal salt reabsorption, and vulnerability to ischemic brain injury.

High-resolution structures show that the Na+-selective cavity (TM4-6) and K+-selective cavity (TM5-10) rearrange according to phosphorylation state, with TM1-2 acting as a signaling lever for E1/E2 allosteric coupling. Kinetic studies identify E1~P formation as rate-limiting and Mg2+ dependence in γ-phosphate transfer. Cardiotonic steroids such as ouabain and digitoxin bind the E2-P state, occluding the ion pathway and exerting positive inotropic effects. Genetic analyses reveal that differences among α1, α2 and α3 isoforms shape phenotypic diversity in cardiac excitation-contraction coupling and neurological disorders.