Recent Advances in Understanding Integrative Control of Potassium Homeostasis

The potassium homeostatic system is very tightly regulated. Recent studies have shed light on the sensing and molecular mechanisms responsible for this tight control. In addition to classic feedback regulation mediated by a rise in extracellular fluid (ECF) [K⁺], there is evidence for a feedforward mechanism: Dietary K⁺ intake is sensed in the gut, and an unidentified gut factor is activated to stimulate renal K⁺ excretion. This pathway may explain renal and extrarenal responses to altered K⁺ intake that occur independently of changes in ECF [K⁺]. Mechanisms for conserving ECF K⁺ during fasting or K⁺ deprivation have been described: Kidney NADPH oxidase activation initiates a cascade that provokes the retraction of K⁺ channels from the cell membrane, and muscle becomes resistant to insulin stimulation of cellular K⁺ uptake. How these mechanisms are triggered by K⁺ deprivation remains unclear. Cellular AMP kinase–dependent protein kinase activity provokes the acute transfer of K⁺ from the ECF to the ICF, which may be important in exercise or ischemia. These recent advances may shed light on the beneficial effects of a high-K⁺ diet for the cardiovascular system.