Na-K ATPase

**Structure and mechanism** - Heteromeric P-type ATPase with an alpha subunit (catalytic; binds Na+, K+, ATP, and ouabain/digoxin) and a beta subunit (trafficking and stability). - Stoichiometry: 3 Na+ out and 2 K+ in per 1 ATP. The pump is electrogenic and contributes a small negative charge (about -3 to -4 mV) to the resting membrane potential. - Cycle: In the E1 state, the pump binds 3 intracellular Na+ and ATP. ATP hydrolysis phosphorylates an aspartate residue on the pump (the "P-type" label), which shifts it to E2. E2 releases Na+ outside and binds 2 extracellular K+. Dephosphorylation returns the pump to E1 and releases K+ inside. - Uses about 20-40% of resting cellular ATP, and more in neurons and in the renal tubule. - It is primary active transport. The Na+ gradient it creates drives secondary active transport (SGLT, Na+/K+/2Cl- cotransporter, Na+/H+ exchanger, Na+/Ca2+ exchanger).

**Physiologic roles** - Maintains the high intracellular K+ and low intracellular Na+ concentrations, which set the resting membrane potential (mostly via K+ leak channels). - Maintains cell volume. If the pump fails (ischemia, ATP depletion), Na+ and water accumulate and the cell swells (cytotoxic edema). - Kidney: located on the basolateral membrane of tubular cells. It drives Na+ reabsorption throughout the nephron and is the basis for the effects of diuretics, which act on apical transporters that depend on the Na+ gradient. - GI tract and glucose absorption: the basolateral pump maintains the Na+ gradient that drives apical SGLT1 in the intestine. This is also the basis for oral rehydration therapy (glucose-coupled Na+ uptake). - Insulin and beta2-agonists stimulate the pump in skeletal muscle, shifting K+ into cells. This is used to treat hyperkalemia (insulin plus glucose, albuterol).

**Pharmacology and clinical correlations** - Cardiac glycosides (digoxin, ouabain) bind the extracellular alpha subunit at the K+ binding site. Inhibition raises intracellular Na+, which reduces Na+/Ca2+ exchanger activity. Intracellular Ca2+ rises, and the result is positive inotropy. Digoxin also increases vagal tone, which slows AV node conduction and lowers heart rate. - Digoxin toxicity: nausea, vomiting, diarrhea, blurry or yellow-green vision (xanthopsia), arrhythmias (PVCs, atrial tachycardia with block, "scooped" ST segments). Hypokalemia worsens toxicity because K+ and digoxin compete for the same binding site. Other risk factors are renal failure and drugs such as quinidine, verapamil, and amiodarone. Treatment is to correct electrolytes, give digoxin-specific Fab fragments (Digibind/DigiFab), and use lidocaine or phenytoin for ventricular arrhythmias. - Hyperkalemia affects the heart through the gradient the pump maintains (peaked T waves, widened QRS). Hypokalemia increases the effect of digoxin. - Loop and thiazide diuretics do not inhibit the pump directly. They block apical transporters (NKCC2, NCC) that rely on the Na+ gradient. - Ischemia and hypoxia cause ATP depletion, pump failure, loss of the gradients, cell swelling, and depolarization. This is an early feature of reversible cell injury. - Hypothyroidism and hyperthyroidism: thyroid hormone upregulates pump expression (part of its thermogenic effect). - Genetic disease: ATP1A2 mutations cause familial hemiplegic migraine type 2. ATP1A3 mutations cause rapid-onset dystonia-parkinsonism and alternating hemiplegia of childhood. ATP1A1 mutations are linked to hypomagnesemia and Charcot-Marie-Tooth. - Related P-type ATPases: SERCA (sarcoplasmic reticulum Ca2+ ATPase), PMCA (plasma membrane Ca2+ ATPase), and H+/K+ ATPase (gastric parietal cells; inhibited by PPIs such as omeprazole).

**High-yield pearls** - 3 Na+ out / 2 K+ in / 1 ATP. - Ouabain and digoxin inhibit it, which leads to increased Ca2+ and increased contractility. - It is the main reason cells have a negative resting potential and a stable volume. - Hypokalemia increases digoxin toxicity. - Key mnemonic: "Digoxin = Dig up the Ca2+ inside the cell by blocking the pump."