The sodium pump (or Na-K-ATPase) is essential to the function of animal cells. Publication of the related calcium pump (SERCA) structure together with several recent results from a variety of approaches allow us to propose a mechanistic model to answer the question: "How does the sodium pump pump?"

Aldosterone-dependent epithelial sodium transport in the distal nephron is mediated by the absorption of sodium through the highly selective, amiloride-sensitive epithelial sodium channel (ENaC) made of three homologous subunits (␣, ␤, and ␥). In human, autosomal recessive mutations of ␣, ␤, or ␥ENaC subunits cause pseudohypoaldosteronism type 1 (PHA-1), a renal salt-wasting syndrome characterized by severe hypovolemia, high plasma aldosterone, hyponatremia, life-threatening hyperkaliemia, and metabolic acidosis. In the mouse, inactivation of ␣ENaC results in failure to clear fetal lung liquid at birth and in early neonatal death, preventing the observation of a PHA-1 renal phenotype. Transgenic expression of ␣ENaC driven by a cytomegalovirus promoter in ␣ENaC(؊͞؊) knockout mice [␣ENaC(؊͞؊)Tg] rescued the perinatal lethal pulmonary phenotype and partially restored Na؉ transport in renal, colonic, and pulmonary epithelia. At days 5-9, however, ␣ENaC(؊͞؊)Tg mice showed clinical features of severe PHA-1 with metabolic acidosis, urinary salt-wasting, growth retardation, and 50% mortality. Adult ␣ENaC(؊͞؊)Tg survivors exhibited a compensated PHA-1 with normal acid͞base and electrolyte values but 6-fold elevation of plasma aldosterone compared with wildtype littermate controls. We conclude that partial restoration of ENaC-mediated Na ؉ absorption in this transgenic mouse results in a mouse model for PHA-1.

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The accessibility of the residues of the sixth transmembrane segment (TM) of the Bufo marinus Na,KATPase K K subunit was explored by cysteine scanning mutagenesis. Methanethiosulfonate reagents reached only the two most extracellular positions (T803, D804) in the native conformation of the Na,K-pump. Palytoxin induced a conductance in all mutants, including D811C, T814C and D815C which showed no active electrogenic transport. After palytoxin treatment, four additional positions (V805, L808, D811 and M816) became accessible to the sulfhydryl reagent. We conclude that one side of the sixth TM helix forms a wall of the palytoxin-induced channel pore and, probably, of the cation pathway from the extracellular side to one of their binding sites. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

The short-term effects (within 4 h) of low doses of intravenous aldosterone or deoxycorticosterone on potassium and sodium urinary excretion were studied by clearance techniques in 24-h adrenalectomized, anesthetized male rats. All animals were substituted with a glucocorticoid (dexamethasone; plasma concentration approximately 6 nM) to maintain normal glomerular filtration rate. The mineralocorticoid effects were studied under various conditions of sodium and potassium load. Mineralocorticoid administration uniformly resulted in antinatriuresis, starting within 30-60 min and, at the peak effect, amounting to 1-2% sodium fractional excretion. The level of antinatriuresis was directly related to the control sodium excretion before aldosterone administration. Mineralocorticoids induced a significant kaliuresis in all groups except one, the one receiving the lowest sodium load. The aldosterone-induced kaliuresis was also related to the sodium load and the control fractional sodium excretion level and was simultaneous with the beginning of the reduced sodium excretion. In control, mineralocorticoid-deprived rats, kaliuresis was not enhanced by increasing the sodium load. Control as well as mineralocorticoid-treated rats responded by an increased kaliuresis following an acute potassium load and by a decreased kaliuresis after 3 days of low potassium diet.