sodium-potassium ATPase

STRUCTURE/MECHANISM: Heterodimer of a catalytic alpha subunit and a glycoprotein beta subunit. It is a P-type ATPase, meaning the alpha subunit is transiently phosphorylated at an aspartate residue during the cycle (E1-P/E2-P conformations). In the E1 state, the pump binds 3 intracellular Na+ and ATP. Phosphorylation shifts it to E2, which releases Na+ outside. In E2, it binds 2 extracellular K+. Dephosphorylation returns it to E1 and releases K+ inside. Net effect is the movement of 1 positive charge out per cycle (electrogenic). It is primary active transport and uses ATP directly.

PHYSIOLOGIC ROLES: - Maintains the Na+ gradient (high extracellular, low intracellular) and K+ gradient (high intracellular, low extracellular). - Contributes directly to the resting membrane potential (about -70 to -90 mV). The main determinant is K+ leak channel permeability, and the pump has a small direct electrogenic contribution. - Drives secondary active transport using the Na+ gradient: SGLT1/2 (glucose), Na+/amino acid cotransporters, Na+-K+-2Cl- (NKCC) in the thick ascending limb, Na+/Ca2+ exchanger (NCX) in cardiac myocytes, and Na+/H+ exchanger. - Regulates cell volume. Pump failure (ischemia/ATP depletion) causes Na+ and water influx, cell swelling, and lysis. - Located on the basolateral membrane of renal tubular epithelium, where it drives Na+ reabsorption (about 65% in the proximal tubule). It also sits on the basolateral membrane of intestinal epithelium. - Consumes a large share of cellular ATP (about 20-40% in most cells, up to about 70% in neurons).

CLINICAL CORRELATES: - Cardiac glycosides (digoxin, ouabain) inhibit the pump by binding the extracellular K+-binding site of the alpha subunit. Hyperkalemia is a risk factor for toxicity because K+ and digoxin compete, and hypokalemia worsens toxicity. Inhibition raises intracellular Na+, which reduces Ca2+ extrusion via NCX. Intracellular Ca2+ rises, producing positive inotropy. Digoxin also increases vagal tone. Toxicity causes nausea, vomiting, yellow-tinted vision (xanthopsia), arrhythmias (PAT with block, ventricular ectopy), and hyperkalemia. Treat with digoxin-specific Fab fragments, correct electrolytes (especially K+ and Mg2+), and use lidocaine or phenytoin for ventricular arrhythmias. - Insulin and beta2-agonists stimulate the pump and shift K+ into cells. This is the basis for treating hyperkalemia with insulin plus glucose and with albuterol. Hypokalemia can result. - Hypokalemia during or after exercise and in thyrotoxic periodic paralysis involves increased pump activity. Thyroid hormone upregulates the pump. - Loop diuretics inhibit NKCC, not the pump, but the pump supplies the gradient for the transporter. Pump-driven Na+ reabsorption underlies diuretic action in several segments. - ATP depletion (ischemia, hypoxia) impairs the pump, causing cellular swelling and reversible injury (an early sign of cell injury in pathology). - Cholera, ORS: Na+-glucose cotransport (SGLT1) depends on the basolateral Na+/K+ ATPase and is preserved in secretory diarrhea, which is why oral rehydration therapy works. - Mutations: ATP1A2 (familial hemiplegic migraine type 2), ATP1A3 (rapid-onset dystonia-parkinsonism, alternating hemiplegia of childhood). - Do not confuse with the H+/K+ ATPase (gastric parietal cell proton pump, inhibited by PPIs) or SERCA (Ca2+ ATPase of the sarcoplasmic reticulum).

HIGH-YIELD PEARLS: 3 Na+ out / 2 K+ in / 1 ATP; inhibited by ouabain and digoxin; K+ competes with digoxin at the binding site; phosphorylated on an aspartate residue (P-type); inhibited by vanadate; and it is the basis for secondary active transport.